Methods and devices for treating primary headache

ABSTRACT

Non-invasive electrical nerve stimulation devices and magnetic stimulation devices are disclosed, along with methods of treating medical disorders using energy that is delivered noninvasively by such devices. The disorders comprise migraine and other primary headaches such as cluster headaches, including sinus symptoms that resemble an immune-mediated response (“sinus” headaches), irrespective of whether those symptoms arise from an allergy that is co-morbid with the headache. The disclosed methods may also be used to treat other disorders that may be co-morbid with migraine headaches, such as anxiety disorders. In preferred embodiments of the disclosed methods, one or both of the patient&#39;s vagus nerves are stimulated non-invasively. In other embodiments, parts of the sympathetic nervous system and/or the adrenal glands are stimulated.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.13/109,250 filed May 17, 2011 now U.S. Pat. No. 8,676,330 issued Mar.18, 2014, which claims the benefit of priority to U.S. ProvisionalApplication Ser. No. 61/471,405 filed Apr. 4, 2011; each of which isincorporated herein by reference in its entirety.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 13/075,746 filed Mar. 30, 2011 now U.S. Pat. No.8,874,205 issued 28 Oct. 2014, which claims the benefit of priority toU.S. Provisional Application Ser. No. 61/451,259 filed Mar. 10, 2011;each of which is incorporated herein by reference in its entirety.

This application also is a Continuation in Part of U.S. patentapplication Ser. No. 13/024,727 filed Feb. 10, 2011 now U.S. Pat. No.9,089,719 issued 28 Jul. 2015, which is a Continuation in Part of U.S.patent application Ser. No. 13/005,005 filed Jan. 12, 2011 now U.S. Pat.No. 8,868,177 issued 21 Oct. 2014, which is a Continuation in Part ofU.S. patent application Ser. No. 12/964,050 filed Dec. 9, 2010, whichclaims the benefit of priority to U.S. Provisional Application Ser. No.61/415,469 filed Nov. 19, 2010; each of which is incorporated herein byreference in its entirety.

This application also is a Continuation in Part application of U.S.patent application Ser. No. 12/859,568 filed Aug. 19, 2010 now U.S. Pat.No. 9,037,247 issued 19 May 2015, which is (1) a Continuation in Part ofU.S. patent application Ser. No. 12/612,177 filed Nov. 4, 2009, now U.S.Pat. No. 8,041,428 issued Oct. 18, 2011, which is a Continuation in Partof U.S. patent application Ser. No. 11/592,095 filed Nov. 2, 2006, nowU.S. Pat. No. 7,725,188 issued May 25, 2010, which claims the benefit ofpriority to U.S. Provisional Application Ser. No. 60/814,312 filed Jun.16, 2006 and U.S. Provisional Application Ser. No. 60/772,361 filed Feb.10, 2006; and (2) a Continuation in Part of U.S. patent application Ser.No. 12/408,131 filed Mar. 20, 2009 now U.S. Pat. No. 8,812,112 issued 19Aug. 2014, which is a Continuation in Part of U.S. patent applicationSer. No. 11/591,340 filed Nov. 1, 2006, now U.S. Pat. No. 7,747,324issued Jun. 29, 2010, which claims the benefit of priority to U.S.Provisional Application Ser. No. 60/814,313 filed Jun. 16, 2006, U.S.Provisional Application Ser. No. 60/786,564 filed Mar. 28, 2006, U.S.Provisional Application Ser. No. 60/772,361 filed Feb. 10, 2006, U.S.Provisional Application Ser. No. 60/736,002 filed Nov. 10, 2005, andU.S. Provisional Application Ser. No. 60/736,001 filed Nov. 10, 2005;each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Itrelates more specifically to the use of non-invasive devices, such aselectrical nerve stimulation devices and magnetic stimulation devices,along with methods of treating medical disorders using energy that isdelivered by such devices. The disorders comprise migraine and otherprimary headaches such as cluster headaches, including sinus symptomsthat resemble an immune-mediated response (“sinus” headaches),irrespective of whether those symptoms arise from an allergy that isco-morbid with the headache. The methods may also be used to treat otherdisorders that may be co-morbid with migraine headaches, such as anxietydisorders in which the nervous system may also be hyper-reactive and inwhich attacks may be triggered by some of the same factors that triggermigraine and asthma attacks. In preferred embodiments of the disclosedmethods, one or both of the patient's vagus nerves are stimulatednon-invasively. In other embodiments, parts of the sympathetic nervoussystem and/or the adrenal glands are stimulated.

Treatments for various infirmities sometime require the destruction ofotherwise healthy tissue in order to produce a beneficial effect.Malfunctioning tissue is identified and then lesioned or otherwisecompromised in order to produce a beneficial outcome, rather thanattempting to repair the tissue to its normal functionality. A varietyof techniques and mechanisms have been designed to produce focusedlesions directly in target nerve tissue, but collateral damage isinevitable.

Other treatments for malfunctioning tissue can be medicinal in nature,but in many cases the patients become dependent upon artificiallysynthesized chemicals. In many cases, these medicinal approaches haveside effects that are either unknown or quite significant.Unfortunately, the beneficial outcomes of surgery and medicines areoften realized at the cost of function of other tissues, or risks ofside effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue holds significant promise for the treatment ofmany ailments, because such stimulation is generally a wholly reversibleand non-destructive treatment.

Nerve stimulation is thought to be accomplished directly or indirectlyby depolarizing a nerve membrane, causing the discharge of an actionpotential; or by hyperpolarization of a nerve membrane, preventing thedischarge of an action potential. Such stimulation may occur afterelectrical energy, or also other forms of energy, are transmitted to thevicinity of a nerve [F. RATTAY. The basic mechanism for the electricalstimulation of the nervous system. Neuroscience 89 (2, 1999):335-346;Thomas HEIMBURG and Andrew D. Jackson. On soliton propagation inbiomembranes and nerves. PNAS 102 (28, 2005): 9790-9795]. Nervestimulation may be measured directly as an increase, decrease, ormodulation of the activity of nerve fibers, or it may be inferred fromthe physiological effects that follow the transmission of energy to thenerve fibers.

One of the most successful applications of modern understanding of theelectrophysiological relationship between muscle and nerves is thecardiac pacemaker. Although origins of the cardiac pacemaker extend backinto the 1800's, it was not until 1950 that the first practical, albeitexternal and bulky, pacemaker was developed. The first truly functional,wearable pacemaker appeared in 1957, and in 1960, the first fullyimplantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by stimulating thesacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No.6,871,099 to WHITEHURST, et al., the disclosure of which is incorporatedherein by reference).

Electrical stimulation of the brain with implanted electrodes has alsobeen approved for use in the treatment of various conditions, includingmovement disorders such as essential tremor and Parkinson's disease. Theprinciple underlying these approaches involves disruption and modulationof hyperactive neuronal circuit transmission at specific sites in thebrain. Unlike potentially dangerous lesioning procedures in whichaberrant portions of the brain are physically destroyed, electricalstimulation is achieved by implanting electrodes at these sites. Theelectrodes are used first to sense aberrant electrical signals and thento send electrical pulses to locally disrupt pathological neuronaltransmission, driving it back into the normal range of activity. Theseelectrical stimulation procedures, while invasive, are generallyconducted with the patient conscious and a participant in the surgery.

However, brain stimulation, and deep brain stimulation in particular, isnot without some drawbacks. The procedure requires penetrating theskull, and inserting an electrode into brain matter using acatheter-shaped lead, or the like. While monitoring the patient'scondition (such as tremor activity, etc.), the position of the electrodeis adjusted to achieve significant therapeutic potential. Next,adjustments are made to the electrical stimulus signals, such asfrequency, periodicity, voltage, current, etc., again to achievetherapeutic results. The electrode is then permanently implanted, andwires are directed from the electrode to the site of a surgicallyimplanted pacemaker. The pacemaker provides the electrical stimulussignals to the electrode to maintain the therapeutic effect. While thetherapeutic results of deep brain stimulation are promising, significantcomplications may arise from the implantation procedure, includingstroke induced by damage to surrounding tissues and theneuro-vasculature.

Most of the above-mentioned applications of electrical stimulationinvolve the surgical implantation of electrodes within a patient. Incontrast, for embodiments of the present invention, the discloseddevices and medical procedures stimulate nerves by transmitting energyto nerves and tissue non-invasively. They may offer the patient analternative that does not involve surgery. A medical procedure isdefined as being non-invasive when no break in the skin (or othersurface of the body, such as a wound bed) is created through use of themethod, and when there is no contact with an internal body cavity beyonda body orifice (e.g., beyond the mouth or beyond the external auditorymeatus of the ear). Such non-invasive procedures are distinguished frominvasive procedures (including minimally invasive procedures) in thatinvasive procedures do involve inserting a substance or device into orthrough the skin or into an internal body cavity beyond a body orifice.For example, transcutaneous electrical nerve stimulation (TENS) isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin (see commonly assignedco-pending US Patent Application 2010/0241188, entitled PercutaneousElectrical Treatment of Tissue to ERRICO et al, which is herebyincorporated by reference).

Potential advantages of non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures generally present fewer problems withbiocompatibility. In cases involving the attachment of electrodes,non-invasive methods have less of a tendency for breakage of leads, andthe electrodes can be easily repositioned if necessary. Non-invasivemethods are sometimes painless or only minimally painful and may beperformed without the need for even local anesthesia. Less training maybe required for use of non-invasive procedures by medical professionals.In view of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace, and the cost of non-invasive procedures may be reducedrelative to comparable invasive procedures.

Electrodes that are applied non-invasively to the surface of the bodyhave a long history, including electrodes that were used to stimulateunderlying nerves [L. A. GEDDES. Historical Evolution of Circuit Modelsfor the Electrode-Electrolyte Interface. Annals of BiomedicalEngineering 25 (1997):1-14]. However, electrical stimulation of nervesin general fell into disfavor in middle of the twentieth century, untilthe “gate theory of pain” was introduced by Melzack and Wall in 1965.This theory, along with advances in electronics, reawakened interest inthe use of implanted electrodes to stimulate nerves, initially tocontrol pain. Screening procedures were then developed to determinesuitable candidates for electrode implantation, which involved firstdetermining whether the patient responded when stimulated withelectrodes applied to the surface of the body in the vicinity of thepossible implant. It was subsequently found that the surface stimulationoften controlled pain so well that there was no need to implant astimulating electrode [Charles Burton and Donald D. Maurer. PainSuppression by Transcutaneous Electronic Stimulation. IEEE Transactionson Biomedical Engineering BME-21(2, 1974): 81-88]. Such non-invasivetranscutaneous electrical nerve stimulation (TENS) was then developedfor treating different types of pain, including pain in a joint or lowerback, cancer pain, post-operative pain, posttraumatic pain, and painassociated with labor and delivery [Steven E. ABRAM. TranscutaneousElectrical Nerve Stimulation. pp 1-10 in: Joel B. Myklebust, ed. Neuralstimulation (Volume 2). Boca Raton, Fla. CRC Press 1985; WALSH D M, LoweA S, McCormack K. Willer J-C, Baxter G D, Allen J M. Transcutaneouselectrical nerve stimulation: effect on peripheral nerve conduction,mechanical pain threshold, and tactile threshold in humans. Arch PhysMed Rehabil 79(1998):1051-1058; J A CAMPBELL. A critical appraisal ofthe electrical output characteristics of ten transcutaneous nervestimulators. Clin. phys. Physiol. Meas. 3(2, 1982): 141-150; U.S. Pat.No. 3,817,254, entitled Transcutaneous stimulator and stimulationmethod, to Maurer; U.S. Pat. No. 4,324,253, entitled Transcutaneous paincontrol and/or muscle stimulating apparatus, to Greene et al; U.S. Pat.No. 4,503,863, entitled Method and apparatus for transcutaneouselectrical stimulation, to Katims; U.S. Pat. No. 5,052,391, entitledHigh frequency high intensity transcutaneous electrical nerve stimulatorand method of treatment, to Silberstone et al; U.S. Pat. No. 6,351,674,entitled Method for inducing electroanesthesia using high frequency,high intensity transcutaneous electrical nerve stimulation, toSilverstone].

As TENS was being developed to treat pain, non-invasive electricalstimulation using surface electrodes was simultaneously developed foradditional therapeutic or diagnostic purposes, which are knowncollectively as electrotherapy. Neuromuscular electrical stimulation(NMES) stimulates normally innervated muscle in an effort to augmentstrength and endurance of normal (e.g., athletic) or damaged (e.g.,spastic) muscle. Functional electrical stimulation (FES) is used toactivate nerves innervating muscle affected by paralysis resulting fromspinal cord injury, head injury, stroke and other neurologicaldisorders, or muscle affected by foot drop and gait disorders. FES isalso used to stimulate muscle as an orthotic substitute, e.g., replace abrace or support in scoliosis management. Another application of surfaceelectrical stimulation is chest-to-back stimulation of tissue, such asemergency defibrillation and cardiac pacing. Surface electricalstimulation has also been used to repair tissue, by increasingcirculation through vasodilation, by controlling edema, by healingwounds, and by inducing bone growth. Surface electrical stimulation isalso used for iontophoresis, in which electrical currents driveelectrically charged drugs or other ions into the skin, usually to treatinflammation and pain, arthritis, wounds or scars. Stimulation withsurface electrodes is also used to evoke a response for diagnosticpurposes, for example in peripheral nerve stimulation (PNS) thatevaluates the ability of motor and sensory nerves to conduct and producereflexes. Surface electrical stimulation is also used inelectroconvulsive therapy to treat psychiatric disorders;electroanesthesia, for example, to prevent pain from dental procedures;and electrotactile speech processing to convert sound into tactilesensation for the hearing impaired. All of the above-mentionedapplications of surface electrode stimulation are intended not to damagethe patient, but if higher currents are used with special electrodes,electrosurgery may be performed as a means to cut, coagulate, desiccate,or fulgurate tissue [Mark R. Prausnitz. The effects of electric currentapplied to skin: A review for transdermal drug delivery. Advanced DrugDelivery Reviews 18 (1996) 395-425].

Despite its attractiveness, non-invasive electrical stimulation of anerve is not always possible or practical. This is primarily because thecurrent state of the art may not be able to stimulate a deep nerveselectively or without producing excessive pain, since the stimulationmay unintentionally stimulate nerves other than the nerve of interest,including nerves that cause pain. For this reason, forms of electricalstimulation other than TENS may be best suited for the treatment ofparticular types of pain [Paul F. WHITE, Shitong Li and Jen W. Chiu.Electroanalgesia: Its Role in Acute and Chronic Pain Management. AnesthAnalg 92(2001):505-13].

For some other electrotherapeutic applications, it has also beendifficult to perform non-invasive stimulation of a nerve, in lieu ofstimulating that nerve invasively. The therapies most relevant to thepresent invention involve electrical stimulation of the vagus nerve inthe neck, which was developed initially for the treatment of epilepsy.The left vagus nerve is ordinarily stimulated at a location within theneck by first surgically implanting an electrode there, then connectingthe electrode to an electrical stimulator [U.S. Pat. No. 4,702,254entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236entitled Vagal nerve stimulation techniques for treatment of epilepticseizures, to OSORIO et al and U.S. Pat. No. 5,299,569 entitled Treatmentof neuropsychiatric disorders by nerve stimulation, to WERNICKE et al;G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brainstimulation, vagal nerve stimulation and transcranial stimulation: Anoverview of stimulation parameters and neurotransmitter release.Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060; GROVES D A,Brown V J. Vagal nerve stimulation: a review of its applications andpotential mechanisms that mediate its clinical effects. NeurosciBiobehav Rev (2005) 29:493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation:current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4].

When it is desired to avoid the surgical implantation of an electrode,vagal nerve stimulation (VNS) may be performed less invasively bypositioning one or more electrodes in the esophagus, trachea, or jugularvein, but with one electrode positioned on the surface of the body [U.S.Pat. No. 7,340,299, entitled Methods of indirectly stimulating the vagusnerve to achieve controlled asystole, to PUSKAS; and U.S. Pat. No.7,869,884, entitled Non-surgical device and methods for trans-esophagealvagus nerve stimulation, to SCOTT et al]. Despite their advantage asbeing non-surgical, such methods nevertheless exhibit otherdisadvantages associated with invasive procedures.

In other patents, non-invasive VNS is disclosed, but at a location otherthan in the neck [e.g., U.S. Pat. No. 4,865,048, entitled Method andapparatus for drug free neurostimulation, to ECKERSON; U.S. Pat. No.6,609,025 entitled Treatment of obesity by bilateral sub-diaphragmaticnerve stimulation to BARRETT et al; U.S. Pat. No. 5,458,625, entitledTranscutaneous nerve stimulation device and method for using same, toKENDALL; U.S. Pat. No. 7,386,347, entitled Electric stimulator foralpha-wave derivation, to Chung et al.; U.S. Pat. No. 7,797,042,entitled Device for applying a transcutaneous stimulus or fortranscutaneous measuring of a parameter, to Dietrich et al.; patentapplication US2010/0057154, entitled Device and Method for theTransdermal Stimulation of a Nerve of the Human Body, to Dietrich et al;US2006/0122675, entitled Stimulator for auricular branch of vagus nerve,to Libbus et al; US2008/0288016, entitled Systems and Methods forStimulating Neural Targets, to Amurthur et al]. However, because suchnon-invasive VNS occurs at a location other than the neck, it is notdirectly comparable to invasive VNS in the neck, for which therapeuticresults are well documented. Among other patents and patentapplications, non-invasive VNS is sometimes mentioned along withinvasive VNS methods, but without addressing the problem ofunintentional stimulation of nerves other than the vagus nerve,particularly nerves that cause pain [e.g., US20080208266, entitledSystem and Method for Treating Nausea and Vomiting by Vagus NerveStimulation, to LESSER et al]. Other patents are vague as to hownon-invasive electrical stimulation in the vicinity of the vagus nervein the neck is to be accomplished [e.g., U.S. Pat. No. 7,499,747,entitled External baroreflex activation, to KIEVAL et al].

The present invention uses electrical nerve stimulation to treatheadaches, particularly non-invasive vagal nerve stimulation in theneck. According to the International Classification of HeadacheDisorders (ICHD-II), there are four types of primary headaches:migraine, tension-type, cluster headache plus other trigeminal autonomiccephalalgias, and other primary headaches (e.g., cough headache,exertional headache). Additional headache types are recognized, but theyare attributable to some causative factor such as head and/or necktrauma, vascular disorder, other intracranial disorders such ashypertension, substance abuse, infection, homeostasis disorder, facialstructural problems (e.g., tooth or ear), psychiatric problems, orcranial neuralgia [Jes OLESEN et al. The International Classification ofHeadache Disorders, Second Edition (ICHD-II). Cephalalgia 24 (Suppl. 1,2004): 1-160]. An overview of the diagnosis and treatment of primary andsome secondary headaches is found in a publication by the BritishAssociation for the Study of Headaches (BASH) [T J STEINER, E AMacGregor, P T G Davies. Guidelines for All Healthcare Professionals inthe Diagnosis and Management of Migraine, Tension-Type, Cluster andMedication-Overuse Headache, 3rd Edition, 2007. BASH. Department ofNeurology, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ GreatBritain].

The present invention is particularly suitable for the treatment ofmigraine and cluster headaches, as well as disorders with which thoseheadaches are co-morbid. According to the ICHD-II, migraine is not ahomogenous entity, but is instead a group of syndromes, some categoriesof which are distinguished by the presence of an aura that usuallyoccurs shortly before pain of the headache. The aura typically lasts for5 minutes to an hour, during which time the patient experiencessensations such as moving zig-zag flashes of light, blind spots ortingling in the hand or face. The features most predictive of thediagnosis of migraine, rather than tension-type headaches, are nausea,photophobia, phonophobia, exacerbation by physical activity and aura.The duration of pain is of little differential diagnostic value fordiscriminating migraine from tension and other types of headache.

Migraine is highly disabling and costly to society, with an annualprevalence of 6-9% among men and 15-17% among women. It occurs in allage groups but reaches a peak in middle age. Migraine headaches oftenoccur on both sides of the head in children, but an adult pattern ofunilateral pain often emerges in adolescence. The pain is often reportedas starting in the occipital/neck regions, later becomingfrontotemporal. It is throbbing and aggravated by physical effort.Approximately 20-30% of migraine sufferers (migraineurs) experience anaura, ordinarily a visual aura. [Bert B. VARGAS, David W. Dodick. TheFace of Chronic Migraine: Epidemiology, Demographics, and TreatmentStrategies. Neurol Clin 27 (2009) 467-479; Peter J. GOADSBY, Richard B.Lipton, Michel D. Ferrari. Migraine—Current understanding and treatment.N Engl J Med 346 (4, 2002): 257-270; Stephen D SILBERSTEIN. Migraine.LANCET 363 (2004):381-391].

Pharmacological administration of triptans is currently the mosteffective treatment for acute migraine headaches (Sumatriptan,Zolmitriptan, Naratriptan, Rizatriptan, Eletriptan, Almotriptan, andFrovatriptan). However, only 30-40% of migraineurs are pain-free twohours after the administration of triptans. Of those who do respond, onein three will experience a migraine recurrence within 24 hours.Furthermore, because triptans constrict cranial blood vessels throughactivation of serotonin 5-HT1B receptors, as a side effect they may alsocause vasoconstriction of coronary vessels. Switching to a differenttriptan might benefit some non-responders, but for many suchmigraineurs, non-migraine-specific rescue drugs that have significantside effects may be the last and potentially ineffective option(opioids, neuroleptics, and/or corticosteroids). Accordingly, migrainetreatment methods are needed that are more effective than triptanpharmaceuticals but that do not exhibit significant side effects[Stephen D Silberstein. Migraine. Lancet 363 (2004):381-391; Peter JGOADSBY, Till Sprenger. Current practice and future directions in theprevention and acute management of migraine. Lancet Neurol 9(2010):285-98; Joel R. SAPER, Alvin E. Lake III, Philip A. Bain, et al. APractice Guide for Continuous Opioid Therapy for Refractory DailyHeadache: Patient Selection, Physician Requirements, and TreatmentMonitoring. Headache 50(2010): 1175-1193].

The diagnosis and treatment of migraine is complicated by the potentialco-morbidity of migraine with other disorders. Those disorders includeischemic stroke and transient ischemic attack (TIA), sub-clinicalcerebral lesions, coronary heart disease, patent foramen ovale,depression, generalized anxiety disorder, panic disorder, bipolardisorders, restless leg syndrome, obesity, epilepsy (co-morbid withaura), fibromyalgia, irritable bowel syndrome, and celiac disease [H. C.DIENER, M. Küper, and T. Kurth. Migraine-associated risks andco-morbidity. J Neurol (2008) 255:1290-1301; Shuu-Jiun WANG, Ping-KunChen and Jong-Ling Fuh. Co-morbidities of migraine. Frontiers inNeurology 1 (Article 16, 2010): pp. 1-9. doi: 10.3389/fneur.2010.00016;Marcelo E. BIGAL, Richard B. Lipton, Philip R. Holland, Peter J.Goadsby. Obesity, migraine, and chronic migraine. Possible mechanisms ofinteraction. Neurology 68 (2007): 1851-1861].

Additional disorders that may be co-morbid with migraine compriseallergic rhinitis, sinusitis, and asthma, the co-morbidity of which islargely responsible for the considerable underreporting and misdiagnosisof migraine. According to the American Migraine Study II, half of theindividuals diagnosed with migraine did not know they were migrainesufferers before diagnosis, and a misdiagnosis of “sinus headache”(rhinosinusitis), rather than migraine, was made in almost ninetypercent of individuals who also had symptoms of facial pain and pressureand/or nasal and sinus congestion. It is estimated that 45% ofindividuals experiencing a migraine headache have a symptom of eithernasal congestion or watery eyes, and this leads to the patient notobtaining treatment for migraine, or to self-treatment withinappropriate, ineffective, or even migraine-enhancing over-the-countersinus medications [LIPTON R B, Diamond S, Reed M, Diamond M L, Stewart WF. Migraine diagnosis and treatment: results from the American MigraineStudy II. Headache 41(7, 2001):638-45; EROSS E, Dodick D, Eross M. TheSinus, Allergy and Migraine Study (SAMS). Headache 47(2, 2007):213-24;Roger K. CADY, David W. Dodick, Howard L. Levine, Curtis P. Schreiber,Eric J. Eross, Michael Setzen, Harvey J. Blumenthal, William R. Lumry,Gary D. Berman, and Paul L. Durham. Sinus Headache: A neurology,otolaryngology, allergy, and primary care consensus on diagnosis andtreatment. Mayo Clin Proc. 80(7, 2005):908-916; Mark E. MEHLE and CurtisP. Schreiber. Sinus Headache, Migraine, and the Otolaryngologist.Otolaryngology—Head and Neck Surgery 133 (2005): 489-496; Curtis P.SCHREIBER, Susan Hutchinson, Christopher J. Webster,

Michael Ames, Mary S. Richardson, Connie Powers. Prevalence of migrainein patients with a history of self-reported or physician-diagnosed“Sinus” Headache. Arch Intern Med. 164(2004): 1769-1772; Roger K. CADYand Curtis P. Schreiber. Sinus problems as a cause of headacherefractoriness and migraine chronification. Current Pain & HeadacheReports 13(2009): 319-325; Gary ISHKANIAN, Harvey Blumenthal,Christopher J. Webster, Mary S. Richardson, and Michael Ames. Efficacyof sumatriptan tablets in migraineurs self-described orphysician-diagnosed as having sinus headache: A randomized,double-blind, placebo-controlled study. Clinical Therapeutics29(2007):99-109; Tarannum M. Lateef, Kathleen R. Merikangas, JianpingHe, Amanda Kalaydjian, Suzan Khoromi, Erin Knight, and Karin B. Nelson.Headache in a National Sample of American Children: Prevalence andCo-morbidity. J Child Neurol 24(5, 2009): 536-543].

In the American Migraine Study II, 40%-70% of respondents with migrainehad co-morbid allergies. Other studies have reported that people withmigraine are 2 to 3.5 times more likely to have co-morbid asthma,particularly if they have a parent with migraine and asthma. Allergicrhinitis (hay fever or nasal allergy) is a histamine-driven response toan allergen, such that when exposed to the allergen, the nasal passagebecomes inflamed and irritated, resulting in a nasal drip. Thathistamine release might be involved in triggering migraine headaches,but stress or environmental insults might also independently triggersimultaneous allergic rhinitis and migraine [Min K U, Bernard Silverman,Nausika Prifti, Wei Ying, Yudy Persaud, and Arlene Schneider. Prevalenceof migraine headaches in patients with allergic rhinitis. Ann AllergyAsthma Immunol. 97(2006):226-230; Gail DAVEY, Philip Sedgwick, WillMaier, George Visick, David P Strachan and H Ross Anderson. Associationbetween migraine and asthma: matched case-control study. British Journalof General Practice 52 (2002): 723-727; AAMODT, A. H., Stovner, L. J.,Langhammer, A., Hagen, K., and Zwart, J. A. (2007). Is headache relatedto asthma, hay fever, and chronic bronchitis? The Head-HUNT Study.Headache 47, 204-212; BECKER, C., Brobert, G. P., Almqvist, P. M.,Johansson, S., Jick, S. S., and Meier, C. R. (2008). The risk of newlydiagnosed asthma in migraineurs with or without previous triptanprescriptions. Headache 48, 606-610; Vincent T. MARTIN, Fred Taylor,Bruce Gebhardt, Mara Tomaszewski, Joel S. Ellison, Geoffrey V. Martin,Linda Levin, Enas Al-Shaikh, Joseph Nicolas, Jonathan A. Bernstein.Allergy and Immunotherapy: Are They Related to Migraine Headache?Headache 51(2011):8-20; Mark E. MEHLE. Allergy and migraine: is there aconnection? Current Opinion in Otolaryngology & Head and Neck Surgery16(2008):265-269; ROBBINS L, Maides J, and Shmaryan D. The Immune Systemand Headache: A Review. The Pain Pract. 19(3, 2009): 47-51].

Thus, a migraineur may exhibit pain that is refractory to treatmentusing currently available conventional methods. A significant number ofmigraineurs also exhibit facial pain and pressure, nasal and sinuscongestion and/or some other symptom that resembles an immune-mediatedresponse. Although those symptoms may be attributable to migraineco-morbid with allergic rhinitis or some other immune-related disorder,the symptoms may in fact arise from the migraine itself.

The present invention provides novel methods and devices for treatingmigraine and other primary headaches (particularly cluster headaches),including sinus symptoms that resemble an immune-mediated response,irrespective of whether those symptoms arise from an allergy that isco-morbid with the headache. The disclosed methods may also be used totreat other disorders that may be co-morbid with migraine, such asanxiety disorders, in which the nervous system may also behyper-reactive and in which attacks may be triggered by some of the samefactors that trigger migraine and asthma attacks.

SUMMARY OF THE INVENTION

In one aspect of the invention, devices and methods are described toproduce therapeutic effects in a patient by utilizing an energy sourcethat transmits energy non-invasively to nervous tissue. In particular,the disclosed devices can transmit energy to, or in close proximity to,a vagus nerve in the neck of the patient, in order to stimulate, blockand/or modulate electrophysiological signals in that nerve. The methodsthat are disclosed herein comprise stimulating the vagus nerve withparticular stimulation waveform parameters, preferably using the nervestimulator devices that are also described herein.

A novel stimulator device is used to modulate electrical activity of avagus nerve or other nerves or tissue. The stimulator comprises a sourceof electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve relative to the nerve axis. Thedevice also comprises continuous electrically conducting media withinwhich the electrodes are in contact, wherein a conducting medium has ashape that conforms to the contour of a target body surface of a patientwhen the medium is applied to the target body surface. In another aspectof the invention, a non-invasive magnetic stimulator device is used tomodulate electrical activity of the vagus nerve or other nerves ortissue.

For the present medical applications, a device is ordinarily applied tothe patient's neck. In a preferred embodiment of the invention, thestimulator comprises two electrodes that lie side-by-side withinseparate stimulator heads, wherein the electrodes are separated byelectrically insulating material. Each electrode and the patient's skinare in continuous contact with an electrically conducting medium thatextends from the skin to the electrode. The conducting media fordifferent electrodes are also separated by electrically insulatingmaterial. In another embodiment of the invention, a non-invasivemagnetic stimulator device is ordinarily applied to the patient's neck.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator, such that the electrodes or magnetic stimulatorproduce an electric current and/or an electric field within the patient.The electrical or magnetic stimulator is configured to induce a peakpulse voltage sufficient to produce an electric field in the vicinity ofa nerve such as a vagus nerve, to cause the nerve to depolarize andreach a threshold for action potential propagation. By way of example,the threshold electric field for stimulation of the nerve may be about 8V/m at 1000 Hz. For example, the device may produce an electric fieldwithin the patient of about 10 to 600 V/m and an electrical fieldgradient of greater than 2 V/m/mm.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of 0 to 30 volts. The current is passedthrough the electrodes in bursts of pulses. There may be 1 to 20 pulsesper burst, preferably five pulses. Each pulse within a burst has aduration of 20 to 1000 microseconds, preferably 200 microseconds. Aburst followed by a silent inter-burst interval repeats at 1 to 5000bursts per second (bps), preferably at 15-50 bps. The preferred shape ofeach pulse is a full sinusoidal wave. The preferred stimulator shapes anelongated electric field of effect that can be oriented parallel to along nerve, such as a vagus nerve in the patient's neck. By selecting asuitable waveform to stimulate the nerve, along with suitable parameterssuch as current, voltage, pulse width, pulses per burst, inter-burstinterval, etc., the stimulator produces a correspondingly selectivephysiological response in an individual patient. Such a suitablewaveform and parameters are simultaneously selected to avoidsubstantially stimulating nerves and tissue other than the target nerve,particularly avoiding the stimulation of nerves that produce pain.

The currents passing through the coils of the magnetic stimulator willsaturate its core (e.g., 0.1 to 2 Tesla magnetic field strength forSupermendur core material). This will require approximately 0.5 to 20amperes of current being passed through each coil, typically 2 amperes,with voltages across each coil of 10 to 100 volts. The current is passedthrough the coils in bursts of pulses, shaping an elongated electricalfield of effect as with the electrode-based stimulator.

Teachings of the present invention demonstrate how the disclosednon-invasive stimulators may be positioned and used against bodysurfaces, particularly at a location on the patient's neck under which avagus nerve is situated. Those teachings also describe the production ofcertain beneficial, therapeutic effects in a patient. An exemplaryteaching is the treatment of migraine and other primary headaches suchas cluster headaches, including sinus symptoms that resemble animmune-mediated response (“sinus” headaches), irrespective of whetherthose symptoms arise from an allergy that is co-morbid with theheadache. The treatment causes patients to experience a very rapidrelief from headache pain, as well as a rapid opening of the nasalpassages within approximately 20 minutes. Effects of the disclosedtreatment method last for 4 to 5 hours or longer, and the method hasnone of the side effects typically associated with pseudoephedrineproducts or other allergy medications. The disclosure also describestreatment of other disorders that may be co-morbid with migraineheadaches, such as anxiety disorders, in which attacks may be triggeredby some of the same factors that trigger migraine and asthma attacks. Inpreferred embodiments of the disclosed methods, a vagus nerve isstimulated non-invasively, but in other embodiments, parts of thesympathetic nervous system and/or the adrenal glands are stimulated.However, it should be understood that application of the methods anddevices is not limited to the examples that are given.

The novel systems, devices and methods for treating conditions using thedisclosed stimulator or other non-invasive stimulation devices are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A is a schematic view of magnetic and electrode-based nerve ortissue modulating devices according to the present invention, whichsupply controlled pulses of electrical current to magnetic coils or toelectrodes, respectively, and each of which are continuously in contactwith a volume that is filled with electrically conducting material.

FIG. 1B is a schematic view of an electrode-based nervestimulating/modulating device in accordance with an embodiment of thepresent disclosure.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora blocking and/or modulating impulses that are applied to a portion orportions of a nerve, in accordance with an embodiment of the presentinvention.

FIGS. 2B and 2C illustrate bursts of sinusoidal pulses of a stimulationwaveform in an embodiment of the present disclosure.

FIGS. 3A and 3B illustrate perspective and cross sectional views of adual-electrode stimulator according to an embodiment of the presentinvention, which is shown to house the stimulator's electrodes andelectronic components.

FIGS. 4A and 4B illustrate exploded and cross sectional views ofalternate embodiments of the head of the dual-electrode stimulator withan aperture screen that is shown in FIGS. 3A and 3B.

FIGS. 4C and 4D illustrate exploded and cross sectional views ofalternate embodiments of the head of the dual-electrode stimulatorwithout an aperture screen.

FIGS. 5A and 5B illustrate a top and bottom perspective view of theouter surface of an alternate embodiment of the dual-electrodestimulator.

FIG. 5C provides a cross sectional view of the stimulator 50 in anembodiment.

FIG. 5D provides a cross sectional view of a magnetic stimulatoraccording to an embodiment of the present disclosure.

FIG. 6 illustrates the approximate position of the housing of astimulator according one embodiment of the present invention, when thestimulator is used to stimulate the vagus nerve in the neck of apatient.

FIG. 7 illustrates the housing of a stimulator according one embodimentof the present invention, as the stimulator is positioned to stimulatethe vagus nerve in a patient's neck via electrically conducting gel (orsome other conducting material), which is applied to the surface of theneck in the vicinity of the identified anatomical structures.

FIGS. 8A and 8B illustrates meningeal blood vessels, nerves, and otherstructures that are involved in the pathophysiology of migraineheadaches, some of which may be affected by stimulation of the vagusnerve according to the present invention.

FIG. 9 illustrates neuronal mechanisms or pathways through whichstimulation of the vagus nerve may reduce the pain of a migraineheadache and/or ameliorate sinus symptoms that resemble animmune-mediated response (“sinus” headaches).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient. The invention is particularly useful for producing appliedelectrical impulses that interact with the signals of one or more nervesto achieve a therapeutic result. In particular, the present disclosuredescribes devices and methods to stimulate a vagus nerve non-invasivelyat a location on the patient's neck.

There is a long-felt but unsolved need to stimulate the vagus nerveelectrically in the neck, totally non-invasively, selectively, andessentially without producing pain. As described below, this isevidenced by the failure of others to solve the problem that is solvedby the present invention, such that investigators abandoned the attemptto non-invasively stimulate electrically in the neck, in favor ofstimulating the vagus nerve at other anatomical locations, or in favorof stimulating the vagus nerve non-electrically. Japanese patentapplication JP2009233024A with a filing date of Mar. 26, 2008, entitledVagus Nerve Stimulation System, to Fukui YOSHIHITO, is concerned withstimulation of the vagus nerve on the surface of the neck to controlheart rate, rather than epilepsy, depression, or other infirmities thatvagal nerve stimulation (VNS) is ordinarily intended to treat.Nevertheless, the approach that is taken by Yoshihito illustrates thedifficulties encountered with non-invasive electrical stimulation thevagus nerve. Yoshihito notes that because electrical stimulation on thesurface of the neck may co-stimulate the phrenic nerve that is involvedwith the control of respiration, the patient hiccups and does notbreathe normally, resulting in “a patient sense of incongruity anddispleasure.” Yoshihito's proposed solution to the problem is tomodulate the timing and intensity of the electrical stimulation at theneck as a function of the respiratory phase, in such a way that theundesirable respiratory effects are minimized. Thus, Yoshihito'sapproach is to compensate for non-selective nerve stimulation, ratherthan find a way to stimulate the vagus nerve selectively. However, suchcompensatory modulation might also prevent the stimulation fromachieving a beneficial effect in treating epilepsy, depression, andother infirmities that are treated with VNS. Furthermore, Yoshihito doesnot address the problem of pain in the vicinity of the stimulationelectrodes. Similar issues could conceivably arise in connection withpossible co-stimulation of the carotid sinus nerve [Ingrid J. M.Scheffers, Abraham A. Kroon, Peter W. de Leeuw. Carotid BaroreflexActivation: Past, Present, and Future. Curr Hypertens Rep12(2010):61-66]. Side effects due to co-activation of muscle that iscontrolled by the vagus nerve itself may also occur, which exemplifyanother type of non-selective stimulation [M Tosato, K Yoshida, E Toftand J J Struijk. Quasi-trapezoidal pulses to selectively block theactivation of intrinsic laryngeal muscles during vagal nervestimulation. J. Neural Eng. 4 (2007): 205-212].

One circumvention of the problem that the present invention solves is tonon-invasively stimulate the vagus nerve at an anatomical location otherthan the neck, where the nerve lies closer to the skin. A preferredalternate location is in or around the ear (tragus, meatus and/orconcha) although other locations have been proposed [Manuel L. KARELL.TENS in the Treatment of Heroin Dependency. The Western Journal ofMedicine 125 (5, 1976):397-398; Enrique C. G. VENTUREYRA. Transcutaneousvagus nerve stimulation for partial onset seizure therapy. A newconcept. Child's Nerv Syst 16 (2000):101-102; T. KRAUS, K. Hosl, O.Kiess, A. Schanze, J. Kornhuber, C. Forster. BOLD fMRI deactivation oflimbic and temporal brain structures and mood enhancing effect bytranscutaneous vagus nerve stimulation. J Neural Transm 114 (2007):1485-1493; POLAK T, Markulin F, Ehlis A C, Langer J B, Ringel T M,Fallgatter A J. Far field potentials from brain stem aftertranscutaneous vagus nerve stimulation: optimization of stimulation andrecording parameters. J Neural Transm 116(10, 2009):1237-1242; U.S. Pat.No. 5,458,625, entitled Transcutaneous nerve stimulation device andmethod for using same, to KENDALL; U.S. Pat. No. 7,797,042, entitledDevice for applying a transcutaneous stimulus or for transcutaneousmeasuring of a parameter, to Dietrich et al.; patent applicationUS2010/0057154, entitled Device and Method for the TransdermalStimulation of a Nerve of the Human Body, to Dietrich et al; See alsothe non-invasive methods and devices that Applicant disclosed incommonly assigned co-pending U.S. patent application Ser. No. 12/859,568entitled Non-invasive Treatment of Bronchial Constriction, to SIMON].However, it is not certain that stimulation in this minor branch of thevagus nerve will have the same effect as stimulation of a main vagusnerve in the neck, where VNS electrodes are ordinarily implanted, andfor which VNS therapeutic procedures produce well-documented results.

Another circumvention of the problem is to substitute electricalstimulation of the vagus nerve in the neck with some other form ofstimulation. For example, mechanical stimulation of the vagus nerve onthe neck has been proposed as an alternative to electrical stimulation[Jared M. HUSTON, Margot Gallowitsch-Puerta, Mahendar Ochani, KantaOchani, Renqi Yuan, Mauricio Rosas-Ballina, Mala Ashok, Richard S.Goldstein, Sangeeta Chavan, Valentin A. Pavlov, Christine N. Metz, HuanYang, Christopher J. Czura, Haichao Wang, Kevin J. Tracey.Transcutaneous vagus nerve stimulation reduces serum high mobility groupbox 1 levels and improves survival in murine sepsis Crit Care Med 35(12, 2007):2762-2768; Artur BAUHOFER and Alexander Torossian. Mechanicalvagus nerve stimulation—A new adjunct in sepsis prophylaxis andtreatment? Crit Care Med 35 (12, 2007):2868-2869; Hendrik SCHMIDT,Ursula Muller-Werdan, Karl Werdan. Assessment of vagal activity duringtranscutaneous vagus nerve stimulation in mice. Crit Care Med 36 (6,2008):1990; see also the non-invasive methods and devices that Applicantdisclosed in commonly assigned co-pending U.S. patent application Ser.No. 12/859,568 entitled Non-invasive Treatment of BronchialConstriction, to SIMON]. However, such mechanical VNS has only beenperformed in animal models, and there is no evidence that suchmechanical VNS would be functionally equivalent to electrical VNS.

Another circumvention of the problem is to use magnetic rather thanpurely electrical stimulation of the vagus nerve in the neck [Q. AZIZ etal. Magnetic Stimulation of Efferent Neural Pathways to the HumanOesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ, Q., J.C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and D. G.Thompson. Esophageal myoelectric responses to magnetic stimulation ofthe human cortex and the extracranial vagus nerve. Am. J. Physiol. 267(Gastrointest. Liver Physiol. 30): G827-G835, 1994; Shaheen HAMDY, QasimAziz, John C. Rothwell, Anthony Hobson, Josephine Barlow, and David G.Thompson. Cranial nerve modulation of human cortical swallowing motorpathways. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35):G802-G808, 1997; Shaheen HAMDY, John C. Rothwell, Qasim Aziz, Krishna D.Singh, and David G. Thompson. Long-term reorganization of human motorcortex driven by short-term sensory stimulation. Nature Neuroscience 1(issue 1, May 1998):64-68; A. SHAFIK. Functional magnetic stimulation ofthe vagus nerve enhances colonic transit time in healthy volunteers.Tech Coloproctol (1999) 3:123-12; see also the non-invasive methods anddevices that Applicant disclosed in co-pending U.S. patent applicationSer. No. 12/859,568 entitled Non-invasive Treatment of BronchialConstriction, to SIMON, as well as co-pending U.S. patent applicationSer. No. 12/964,050 entitled Magnetic Stimulation Devices and Methods ofTherapy, to SIMON et al]. Magnetic stimulation might functionallyapproximate electrical stimulation. However, magnetic stimulation hasthe disadvantage that it ordinarily requires complex and expensiveequipment, and the duration of stimulation may be limited by overheatingof the magnetic stimulator. Furthermore, in some cases, magneticstimulation in the neck might also inadvertently stimulate nerves otherthan the vagus nerve, such as the phrenic nerve [SIMILOWSKI, T., B.Fleury, S. Launois, H. P. Cathala, P. Bouche, and J. P. Derenne.Cervical magnetic stimulation: a new painless method for bilateralphrenic nerve stimulation in conscious humans. J. Appl. Physiol. 67(4):1311-1318, 1989; Gerrard F. RAFFERTY, Anne Greenough, Terezia Manczur,Michael I. Polkey, M. Lou Harris, Nigel D. Heaton, Mohamed Rela, andJohn Moxham. Magnetic phrenic nerve stimulation to assess diaphragmfunction in children following liver transplantation. Pediatr Crit CareMed 2001, 2:122-126; W. D-C. MAN, J. Moxham, and M. I. Polkey. Magneticstimulation for the measurement of respiratory and skeletal musclefunction. Eur Respir J 2004; 24: 846-860]. Furthermore, magneticstimulation may also stimulate nerves that cause pain. Other stimulatorsthat make use of magnetic fields might also be used, but they too arecomplex and expensive and may share other disadvantages with moreconventional magnetic stimulators [U.S. Pat. No. 7,699,768, entitledDevice and method for non-invasive, localized neural stimulationutilizing hall effect phenomenon, to Kishawi et al].

Transcutaneous electrical stimulation (as well as magnetic stimulation)can be unpleasant or painful, in the experience of patients that undergosuch procedures. The quality of sensation caused by stimulation dependsstrongly on current and frequency, such that currents barely greaterthan the perception threshold generally cause painless sensationsdescribed as tingle, itch, vibration, buzz, touch, pressure, or pinch,but higher currents can cause sharp or burning pain. As the depth ofpenetration of the stimulus under the skin is increased (e.g., to deepernerves such as the vagus nerve), any pain will generally begin orincrease. Strategies to reduce the pain include: use of anestheticsplaced on or injected into the skin near the stimulation and placementof foam pads on the skin at the site of stimulation [Jeffrey J.BORCKARDT, Arthur R. Smith, Kelby Hutcheson, Kevin Johnson, Ziad Nahas,Berry Anderson, M. Bret Schneider, Scott T. Reeves, and Mark S. George.Reducing Pain and Unpleasantness During Repetitive Transcranial MagneticStimulation. Journal of ECT 2006; 22:259-264], use of nerve blockades[V. HAKKINEN, H. Eskola, A. Yli-Hankala, T. Nurmikko and S. Kolehmainen.Which structures are sensitive to painful transcranial stimulation?Electromyogr. clin. Neurophysiol. 1995, 35:377-383], the use of veryshort stimulation pulses [V. SUIHKO. Modelling the response of scalpsensory receptors to transcranial electrical stimulation. Med. Biol.Eng. Comput., 2002, 40, 395-401], decreasing current density byincreasing electrode size [Kristof VERHOEVEN and J. Gert van Dijk.Decreasing pain in electrical nerve stimulation. ClinicalNeurophysiology 117 (2006) 972-978], using a high impedance electrode[N. SHA, L. P. J. Kenney, B. W. Heller, A. T. Barker, D. Howard and W.Wang. The effect of the impedance of a thin hydrogel electrode onsensation during functional electrical stimulation. Medical Engineering& Physics 30 (2008): 739-746] and providing patients with the amount ofinformation that suits their personalities [Anthony DELITTO, Michael JStrube, Arthur D Shulman, Scott D Minor. A Study of Discomfort withElectrical Stimulation. Phys. Ther. 1992; 72:410-424]. U.S. Pat. No.7,614,996, entitled Reducing discomfort caused by electricalstimulation, to RIEHL discloses the application of a secondary stimulusto counteract what would otherwise be an uncomfortable primary stimulus.

Additional considerations related to pain resulting from the stimulationare as follows. When stimulation is repeated over the course of multiplesessions, patients may adapt to the pain and exhibit progressively lessdiscomfort. Patients may be heterogeneous with respect to theirthreshold for pain caused by stimulation, including heterogeneityrelated to gender and age. Electrical properties of an individual's skinvary from day to day and may be affected by cleaning, abrasion, and theapplication of various electrode gels and pastes. Skin properties mayalso be affected by the stimulation itself, as a function of theduration of stimulation, the recovery time between stimulation sessions,the transdermal voltage, the current density, and the power density. Theapplication of multiple electrical pulses can result in differentperception or pain thresholds and levels of sensation, depending on thespacing and rate at which pulses are applied. The separation distancebetween two electrodes determines whether sensations from the electrodesare separate, overlap, or merge. The limit for tolerable sensation issometimes said to correspond to a current density of 0.5 mA/cm², but inreality the functional relationship between pain and current density isvery complicated. Maximum local current density may be more important inproducing pain than average current density, and local current densitygenerally varies under an electrode, e.g., with greater currentdensities along edges of the electrode or at “hot spots.” Furthermore,pain thresholds can have a thermal and/or electrochemical component, aswell as a current density component. Pulse frequency plays a significantrole in the perception of pain, with muscle contraction being involvedat some frequencies and not others, and with the spatial extent of thepain sensation also being a function of frequency. The sensation is alsoa function of the waveform (square-wave, sinusoidal, trapezoidal, etc.),especially if pulses are less than a millisecond in duration [Mark R.PRAUSNITZ. The effects of electric current applied to skin: A review fortransdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996):395-425].

Considering that there are so many variables that may influence thelikelihood of pain during non-invasive electrical stimulation (detailedstimulus waveform, frequency, current density, electrode type andgeometry, skin preparation, etc.), considering that these same variablesmust be simultaneously selected in order to independently produce adesired therapeutic outcome by vagal nerve stimulation, and consideringthat one also wishes to selectively stimulate the vagus nerve (e.g.,avoid stimulating the phrenic nerve), it is understandable that prior tothe present disclosure, no one has described devices and methods forstimulating the vagus nerve electrically in the neck, totallynon-invasively, selectively, and without causing substantial pain.

Applicant discovered the disclosed devices and methods in the course ofexperimentation with a magnetic stimulation device that was disclosed inApplicant's commonly assigned co-pending U.S. patent application Ser.No. 12/964,050 entitled Magnetic Stimulation Devices and Methods ofTherapy, to SIMON et al. Thus, combined elements in the invention do notmerely perform the function that the elements perform separately (viz.,perform therapeutic VNS, minimize stimulation pain, or stimulate thevagus nerve selectively), and one of ordinary skill in the art would nothave combined the claimed elements by known methods because thearchetypal magnetic stimulator was known only to Applicant. Thatstimulator used a magnetic coil, embedded in a safe and practicalconducting medium that was in direct contact with arbitrarily-orientedpatient's skin, which had not been described in its closest art [RafaelCARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering 48 (4, 2001): 434-441; Rafael CarbunaruFAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999. (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Referring now to FIG. 1, FIG. 1A is a schematic diagram of Applicant'sabove-mentioned magnetic nerve stimulating/modulating device 301 fordelivering impulses of energy to nerves for the treatment of medicalconditions. As shown, device 301 may include an impulse generator 310; apower source 320 coupled to the impulse generator 310; a control unit330 in communication with the impulse generator 310 and coupled to thepower source 320; and a magnetic stimulator coil 341 coupled via wiresto impulse generator coil 310. The stimulator coil 341 is toroidal inshape, due to its winding around a toroid of core material.

Although the magnetic stimulator coil 341 is shown in FIG. 1A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 shown in FIG. 1A representsall the magnetic stimulator coils of the device collectively. In apreferred embodiment, coil 341 actually contains two coils that may beconnected either in series or in parallel to the impulse generator 310.

The item labeled in FIG. 1A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is shown in FIG. 5D, the conducting medium with whichthe coil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is adapted herein foruse with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a deep nerve such as a vagusnerve in the neck of a patient. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient thanstimulator devices that are currently known in the art. Conversely, fora given amount of pain or discomfort on the part of the patient (e.g.,the threshold at which such discomfort or pain begins), the designachieves a greater depth of penetration of the stimulus under the skin.

FIG. 1B shows an electrode-based nerve stimulating/modulating device 302for delivering impulses of energy to nerves for the treatment of medicalconditions. As shown, device 302 may include an impulse generator 310; apower source 320 coupled to the impulse generator 310; a control unit330 in communication with the impulse generator 310 and coupled to thepower source 320; and electrodes 342 coupled via wires 345 to impulsegenerator 310. In a preferred embodiment, the same impulse generator310, power source 320, and control unit 330 may be used for either themagnetic stimulator 301 or the electrode-based stimulator 302, allowingthe user to change parameter settings depending on whether coils 341 orthe electrodes 342 are attached.

Although a pair of electrodes 342 is shown in FIG. 1B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 342 that are shown in FIG. 1Brepresent all electrodes of the device collectively.

The item labeled in FIG. 1B as 352 is a volume, contiguous with anelectrode 342, that is filled with electrically conducting medium. Asshown, the medium is also deformable such that it is form-fitting whenapplied to the surface of the body. Thus, the sinuousness or curvatureshown at the outer surface of the electrically conducting medium 352corresponds also to sinuousness or curvature on the surface of the body,against which the conducting medium 352 is applied, so as to make themedium and body surface contiguous. As described below in connectionwith a preferred embodiment, the volume 352 is electrically connected tothe patient at a target skin surface in order to shape the currentdensity passed through an electrode 342 that is needed to accomplishstimulation of the patient's nerve or tissue. As also described below inconnection with embodiments of the invention, conducting medium withwhich the electrode 342 is in contact need not completely surround anelectrode.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 342. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, both of which areincorporated herein by reference, relating to stimulation of neurons ofthe sympathetic nervous system to attenuate an immune response, containdescriptions of pulse generators that may be applicable to the presentinvention. By way of example, a pulse generator is also commerciallyavailable, such as Agilent 33522A Function/Arbitrary Waveform Generator,Agilent Technologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif.95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals, analog-to-digitalconverters for digitizing externally supplied analog signals,communication devices for the transmission and receipt of data to andfrom external devices such as printers and modems that comprise part ofthe system, hardware for generating the display of information onmonitors that comprise part of the system, and busses to interconnectthe above-mentioned components. Thus, the user may operate the system bytyping instructions for the control unit 330 at a device such as akeyboard and view the results on a device such as the system's computermonitor, or direct the results to a printer, modem, and/or storage disk.Control of the system may be based upon feedback measured fromexternally supplied physiological or environmental signals.Alternatively, the control unit 330 may have a compact and simplestructure, for example, wherein the user may operate the system usingonly an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmurto, Przemystaw Ptonecki, Jacek Starzyński, StanislawWincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, IOS Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

Referring now to FIG. 2, FIG. 2A illustrates an exemplary electricalvoltage/current profile for a stimulating, blocking and/or modulatingimpulse applied to a portion or portions of selected nerves inaccordance with an embodiment of the present invention. For thepreferred embodiment, the voltage and current refer to those that areproduced non-invasively within the patient by the magnetic stimulator orelectrodes. As shown, a suitable electrical voltage/current profile 400for the blocking and/or modulating impulse 410 to the portion orportions of a nerve may be achieved using pulse generator 310. In apreferred embodiment, the pulse generator 310 may be implemented using apower source 320 and a control unit 330 having, for instance, aprocessor, a clock, a memory, etc., to produce a pulse train 420 to thecoil 341 or electrodes 342 that deliver the stimulating, blocking and/ormodulating impulse 410 to the nerve. Nerve stimulating/modulating device301 or 302 may be externally powered and/or recharged may have its ownpower source 320. The parameters of the modulation signal 400, such asthe frequency, amplitude, duty cycle, pulse width, pulse shape, etc.,are preferably programmable. An external communication device may modifythe pulse generator programming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes,the device disclosed in patent publication No. US2005/0216062 (theentire disclosure of which is incorporated herein by reference) may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type the user wishes, who can then observe the effectof this signal on a substance being treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 20 microseconds or greater, suchas about 20 microseconds to about 1000 microseconds. For example, theelectric field induced by the device within tissue in the vicinity of anerve is 10 to 600 V/m, preferably around 300 V/m. The gradient of theelectric field may be greater than 2 V/m/mm. More generally, thestimulation device produces an electric field in the vicinity of thenerve that is sufficient to cause the nerve to depolarize and reach athreshold for action potential propagation, which is approximately 8 V/mat 1000 Hz.

An objective of the stimulators disclosed herein is to provide bothnerve fiber selectivity and spatial selectivity. Spatial selectivity maybe achieved in part through the design of the electrode or coilconfiguration, and nerve fiber selectivity may be achieved in partthrough the design of the stimulus waveform, but designs for the twotypes of selectivity are intertwined. This is because, for example, awaveform may selectively stimulate only one of two nerves whether theylie close to one another or not, obviating the need to focus thestimulating signal onto only one of the nerves [GRILL W and Mortimer JT. Stimulus waveforms for selective neural stimulation. IEEE Eng. Med.Biol. 14 (1995): 375-385].

To date, the selection of stimulation waveform parameters for vagalnerve stimulation (VNS) has been highly empirical, in which theparameters are varied about some initially successful set of parameters,in an effort to find an improved set of parameters for each patient. Amore efficient approach to selecting stimulation parameters might be toselect a stimulation waveform that mimics electrical activity in theregions of the brain that one is attempting stimulate indirectly, in aneffort to entrain the naturally occurring electrical waveform, assuggested in patent number U.S. Pat. No. 6,234,953, entitledElectrotherapy device using low frequency magnetic pulses, to THOMAS etal. and application number US20090299435, entitled Systems and methodsfor enhancing or affecting neural stimulation efficiency and/orefficacy, to GLINER et al. One may also vary stimulation parametersiteratively, in search of an optimal setting [U.S. Pat. No. 7,869,885,entitled Threshold optimization for tissue stimulation therapy, toBegnaud, et al]. However, some VNS stimulation waveforms, such as thosedescribed herein, are discovered by trial and error, and thendeliberately improved upon.

Invasive vagal nerve stimulation typically uses square wave pulsesignals. The typical waveform parameter values for VNS therapy forepilepsy and depression are: a current between 1 and 2 mA, a frequencyof between 20 and 30 Hz, a pulse width of 250-500 microseconds, and aduty cycle of 10% (signal ON time of 30 s, and a signal OFF time to 5min). Output current is gradually increased from 0.25 mA to the maximumtolerable level (maximum, 3.5 mA), with typical therapeutic settingsranging from 1.0 to 1.5 mA. Greater output current is associated withincreased side effects, including voice alteration, cough, a feeling ofthroat tightening, and dyspnea. Frequency is typically 20 Hz indepression and 30 Hz in epilepsy. The therapy is adjusted in a gradual,systematic fashion to individualize therapy for each patient. To treatmigraine headaches, typical VNS parameters are a current of 0.25 to 1mA, a frequency of 30 Hz, a pulse width of 500 microseconds, and an ‘ON’time of 30 s every 5 min. To treat migraine plus epilepsy, typicalparameters are 1.75 mA, a frequency of 20 Hz, a pulse width of 250microseconds, and ‘ON’ time of 7 s followed by an ‘OFF’ time of 12 s. Totreat mild to moderate Alzheimer's disease, typical VNS waveformparameters are: a current of 0.25 to 0.5 mA, a frequency of 20 Hz, apulse width of 500 microseconds, and an ‘ON’ time of 30 s every 5 min.[ANDREWS, A. J., 2003. Neuromodulation. I. Techniques-deep brainstimulation, vagus nerve stimulation, and transcranial magneticstimulation. Ann. N. Y. Acad. Sci. 993, 1-13; LABINER, D. M., Ahern, G.L., 2007. Vagus nerve stimulation therapy in depression and epilepsy:therapeutic parameter settings. Acta. Neurol. Scand. 115, 23-33; G. C.ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation,vagal nerve stimulation and transcranial stimulation: An overview ofstimulation parameters and neurotransmitter release. Neuroscience andBiobehavioral Reviews 33 (2009) 1042-1060]. Applicant found that thesesquare waveforms are not ideal for non-invasive VNS stimulation as theyproduce excessive pain.

Prepulses and similar waveform modifications have been suggested asmeans to improve selectivity of vagus and other nerve stimulationwaveforms, but Applicant did not find them ideal [Aleksandra VUCKOVIC,Marco Tosato and Johannes J Struijk. A comparative study of threetechniques for diameter selective fiber activation in the vagal nerve:anodal block, depolarizing prepulses and slowly rising pulses. J. NeuralEng. 5 (2008): 275-286; Aleksandra VUCKOVIC, Nico J. M. Rijkhoff, andJohannes J. Struijk. Different Pulse Shapes to Obtain Small FiberSelective Activation by Anodal Blocking—A Simulation Study. IEEETransactions on Biomedical Engineering 51(5, 2004):698-706; KristianHENNINGS. Selective Electrical Stimulation of Peripheral Nerve Fibers:Accommodation Based Methods. Ph.D. Thesis, Center for Sensory-MotorInteraction, Aalborg University, Aalborg, Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive VNS stimulation [M. I.JOHNSON, C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesiceffects of different pulse patterns of transcutaneous electrical nervestimulation on cold-induced pain in normal subjects. Journal ofPsychosomatic Research 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340,entitled Stimulation design for neuromodulation, to De Ridder]. However,bursts of sinusoidal pulses are a preferred stimulation waveform, asshown in FIGS. 2B and 2C. As seen there, individual sinusoidal pulseshave a period of τ, and a burst consists of N such pulses. This isfollowed by a period with no signal (the inter-burst period). Thepattern of a burst plus followed by silent inter-burst period repeatsitself with a period of T. For example, the sinusoidal period □ τ may be200 microseconds; the number of pulses per burst may be N=5; and thewhole pattern of burst followed by silent inter-burst period may have aperiod of T=40000 microseconds (a much smaller value of T is shown inFIG. 2C to make the bursts discernable). Applicant is unaware of such awaveform having been used with vagal nerve stimulation, but a similarwaveform has been used to stimulate muscle as a means of increasingmuscle strength in elite athletes. However, for the muscle strengtheningapplication, the currents used (200 mA) may be very painful and twoorders of magnitude larger than what is disclosed herein for VNS.Furthermore, the signal used for muscle strengthening may be other thansinusoidal (e.g., triangular), and the parameters τ, N, and T may alsobe dissimilar from the values exemplified above [A. DELITTO, M. Brown,M. J. Strube, S. J. Rose, and R. C. Lehman. Electrical stimulation ofthe quadriceps femoris in an elite weight lifter: a single subjectexperiment. Int J Sports Med 10(1989):187-191; Alex R WARD, NataliyaShkuratova. Russian Electrical Stimulation: The Early Experiments.Physical Therapy 82 (10, 2002): 1019-1030; Yocheved LAUFER and MichalElboim. Effect of Burst Frequency and Duration of Kilohertz-FrequencyAlternating Currents and of Low-Frequency Pulsed Currents on Strength ofContraction, Muscle Fatigue, and Perceived Discomfort. Physical Therapy88 (10, 2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181]. Byway of example, the electric field shown in FIGS. 2B and 2C may have anE_(max) value of 17 V/m, which is sufficient to stimulate the vagusnerve but is significantly lower than the threshold needed to stimulatesurrounding muscle.

In order to compare the electrical stimulator that is disclosed hereinwith existing electrodes and stimulators that have been used fornon-invasive electrical stimulation, it is useful to first summarize therelevant physics of electric fields and currents that are produced bythe electrodes. According to Maxwell's equation (Ampere's law withMaxwell correction): ∇×B=J+∈(∂E□□∂t), where B is the magnetic field, Jis the electrical current density, E is the electric field, ∈ is thepermittivity, and t is time [Richard P. FEYNMAN, Robert B. Leighton, andMatthew Sands. The Feynman Lectures on Physics. Volume II.Addison-Wesley Publ. Co. (Reading Mass., 1964), page 15-15].

According to Faraday's law, ∇×E=−∂B□∂t□□ However, for present purposes,changes in the magnetic field B may be ignored, so ∇×E=0, and E maytherefore be obtained from the gradient of a scalar potential Φ:□E=−∇Φ.In general, the scalar potential Φ and the electric field E arefunctions of position (r) and time (t).

The electrical current density J is also a function of position (r) andtime (t), and it is determined by the electric field and conductivity asfollows, where the conductivity σ is generally a tensor and a functionof position (r): J=σE=−σ∇Φ.

Because ∇·∇×B=0, Ampere's law with Maxwell's correction may be writtenas: ∇·J+∇·∈ (∂E□□∂t)=0. If the current flows in material that isessentially unpolarizable (i.e., is presumed not to be a dielectric sothat ∈=0), substitution of the expression for J into the aboveexpression for Ampere's law gives −∇·(σ∇Φ)=0, which is a form ofLaplace's equation. If the conductivity of material in the device (orpatient) is itself a function of the electric field or potential, thenthe equation becomes non-linear, which could exhibit multiple solutions,frequency multiplication, and other such non-linear behavior. Theequation has been solved analytically for special electrodeconfigurations, but for more general electrode configurations, it mustbe solved numerically [Petrus J. CILLIERS. Analysis of the currentdensity distribution due to surface electrode stimulation of the humanbody. Ph.D. Dissertation, Ohio State University, 1988. (UMI MicroformNumber: 8820270, UMI Company, Ann Arbor Mich.); Martin REICHEL, TeresaBreyer, Winfried Mayr, and Frank Rattay. Simulation of theThree-Dimensional Electrical Field in the Course of FunctionalElectrical Stimulation. Artificial Organs 26(3, 2002):252-255; CameronC. McINTYRE and Warren M. Grill. Finite Element Analysis of theCurrent-Density and Electric Field Generated by Metal Microelectrodes.Annals of Biomedical Engineering 29 (2001): 227-235; A. PATRICIU, T. P.DeMonte, M. L. G. Joy, J. J. Struijk. Investigation of current densitiesproduced by surface electrodes using finite element modeling and currentdensity imaging. Proceedings of the 23rd Annual EMBS InternationalConference, Oct. 25-28, 2001, Istanbul, Turkey: 2403-2406; Yong H U, X BXie, L Y Pang, X H Li K D K Luk. Current Density Distribution UnderSurface Electrode on Posterior Tibial Nerve Electrical Stimulation.Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27thAnnual Conference Shanghai, China, Sep. 1-4, 2005: 3650-3652]. Theequation has also been solved numerically in order to compare differentelectrode shapes and numbers [Abhishek DATTA, Maged Elwassif, FortunatoBattaglia and Marom Bikson. Transcranial current stimulation focalityusing disc and ring electrode configurations: FEM analysis. J. NeuralEng. 5 (2008) 163-174; Jay T. RUBENSTEIN, Francis A. Spelman, Mani Somaand Michael F. Suesserman. Current Density Profiles of Surface Mountedand Recessed Electrodes for Neural Prostheses. IEEE Transactions onBiomedical Engineering BME-34 (11, 1987): 864-875; David A. KSIENSKI. AMinimum Profile Uniform Current Density Electrode. IEEE Transactions onBiomedical Engineering 39 (7, 1992): 682-692; Andreas KUHN, ThierryKeller, Silvestro Micera, Manfred Morari. Array electrode design fortranscutaneous electrical stimulation: A simulation study. MedicalEngineering & Physics 31 (2009) 945-951]. The calculated electricalfields may be confirmed using measurements using a phantom [A. M.SAGI_DOLEV, D. Prutchi and R. H. Nathan. Three-dimensional currentdensity distribution under surface stimulation electrodes. Med. andBiol. Eng. and Comput. 33(1995): 403-408].

If capacitive effects cannot be ignored, an additional term involvingthe time-derivative of the gradient of the potential appears in the moregeneral expression, as obtained by substituting the expressions for Jand E into the divergence of Ampere's law with Maxwell's correction:—∇·(σ∇Φ)−∇·(∈∇(∂Φ/∇∂t))∇=0

The permittivity ∈ is a function of position (r) and is generally atensor. It may result from properties of the body and may also be aproperty of the electrode design [L. A. GEDDES, M. Hinds and K. S.Foster. Stimulation with capacitor electrodes. Med. and Biol. Eng. andComput. 25(1987):359-360]. As a consequence of such a term, the waveformof the electrical potential at points within the body will generally bealtered relative to the waveform of the voltage signal(s) applied to theelectrode(s). Furthermore, if the permittivity of a material in thedevice itself (or patient) is a function of the electric field orpotential, then the equation becomes non-linear, which could exhibitmultiple solutions, frequency multiplication, and other such non-linearbehavior. This time-dependent equation has been solved numerically [KUHNA, Keller T. A 3D transient model for transcutaneous functionalelectrical stimulation. Proc. 10th Annual Conference of theInternational FES Society July 2005—Montreal, Canada: pp. 1-3; AndreasKUHN, Thierry Keller, Marc Lawrence, Manfred Morari. A model fortranscutaneous current stimulation: simulations and experiments. MedBiol Eng Comput 47(2009):279-289; N. FILIPOVIC, M. Nedeljkovic, A.Peulic. Finite Element Modeling of a Transient Functional ElectricalStimulation. Journal of the Serbian Society for Computational Mechanics1 (1, 2007):154-163; Todd A. KUIKEN, Nikolay S. Stoykov, Milica Popovic,Madeleine Lowery and Allen Taflove. Finite Element Modeling ofElectromagnetic Signal Propagation in a Phantom Arm. IEEE Transactionson Neural Systems and Rehabilitation Engineering 9 (4, 2001): 346-354].

In any case, Dirichlet (D) boundary conditions define voltage sources,and Neumann (N) boundary conditions describe the behavior of theelectric field at the crossover boundary from skin to air, as follows:N:∂Φ/∂n□=□σ(r)andD:Φ=□V(t)

where n denotes the outward pointing normal vector, i.e., the vectororthogonal to the boundary curve; and V(t) denotes the voltage appliedto an electrode. Thus, no conduction current can flow across anair/conductor interface, so according to the interfacial boundaryconditions, the component of any current normal to the an air/conductorinterface must be zero. In constructing the above differential equationfor Φ as a function of time, the divergence of J is taken, whichsatisfies the continuity equation: ∇·J=−∂ρ/∂t, where ρ is the chargedensity. Conservation of charge requires that sides of this equationequal zero everywhere except at the surface of the electrode wherecharge is impressed upon the system (injected or received).

It is an objective of the present invention to shape an elongatedelectric field of effect that can be oriented parallel to a long nervesuch as the vagus nerve in the neck. The term “shape an electric field”as used herein means to create an electric field or its gradient that isgenerally not radially symmetric at a given depth of stimulation in thepatient, especially a field that is characterized as being elongated orfinger-like, and especially also a field in which the magnitude of thefield in some direction may exhibit more than one spatial maximum (i.e.may be bimodal or multimodal) such that the tissue between the maximamay contain an area across which current flow is restricted. Shaping ofthe electric field refers both to the circumscribing of regions withinwhich there is a significant electric field and to configuring thedirections of the electric field within those regions. Our inventiondoes so by configuring elements that are present within the equationsthat were summarized above, comprising (but not limited to) thefollowing exemplary configurations that may be used alone or incombination.

First, different contours or shapes of the electrodes affect ∇·J. Forexample, charge is impressed upon the system (injected or received)differently if an electrode is curved versus flat, or if there are morethan two electrodes in the system.

Second, values of the voltage V(t) in the above boundary condition ismanipulated to shape the electric field. For example, if the devicecontains two pairs of electrodes that are perpendicular or at a variableangle with respect to one another, the waveform of the voltage acrossone pair of electrodes may be different than the waveform of the voltageacross the second pair, so that the superimposed electric fields thatthey produce may exhibit beat frequencies, as has been attempted withelectrode-based stimulators [U.S. Pat. No. 5,512,057, entitledInterferential stimulator for applying localized stimulation, to REISSet al.], and acoustic stimulators [U.S. Pat. No. 5,903,516, entitledAcoustic force generator for detection, imaging and informationtransmission using the beat signal of multiple intersecting sonic beams,to GREENLEAF et al].

Third, the scalar potential Φ in the above equation ∂Φ/∂n□=σ(r) may bemanipulated to shape the electric field. For example, this isaccomplished by changing the boundaries of conductor/air (ornon-conductor) interfaces, thereby creating different boundaryconditions. For example, the conducting material may pass throughconducting apertures in an insulated mesh before contacting thepatient's skin, creating thereby an array of electric field maxima. Asanother example, an electrode may be disposed at the end of a long tubethat is filled with conducting material, or the electrode may besituated at the bottom of a curved cup that is filled with conductingmaterial. In those cases the dimensions of the tube or cup would affectthe resulting electric fields and currents.

Fourth, the conductivity σ (in the equation J=σE) may be variedspatially within the device by using two or more different conductingmaterials that are in contact with one another, for given boundaryconditions. The conductivity may also be varied by constructing someconducting material from a semiconductor, which allows for adjustment ofthe conductivity in space and in time by exposure of the semiconductorto agents to which they are sensitive, such as electric fields, light atparticular wavelengths, temperature, or some other environmentalvariable over which the user of the device has control. For the specialcase in which the semiconductor's conductivity may be made to approachzero, that would approximate the imposition of an interfacial boundarycondition as described in the previous paragraph.

Fifth, a dielectric material having a high permittivity ∈, such asMylar, neoprene, titanium dioxide, or strontium titanate, may be used inthe device, for example, in order to permit capacitative electricalcoupling to the patient's skin. Changing the permittivity in conjunctionalong with changing the waveform V(t) would especially affect operationof the device, because the permittivity appears in a term that is afunction of the time-derivative of the electric potential:∇·(∈∇(∂φ/∂t))□.

In configurations of the present invention, an electrode is situated ina container that is filled with conducting material. The disclosurebelow applies as well to conducting material within the magneticstimulation device. In one embodiment, the container contains holes sothat the conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 in FIG. 1A or 352 in FIG. 1B may comprise achamber surrounding the electrode, filled with a conductive gel that hasthe approximate viscosity and mechanical consistency of gel deodorant(e.g., Right Guard Clear Gel from Dial Corporation, 15501 N. DialBoulevard, Scottsdale Ariz. 85260, one composition of which comprisesaluminum chlorohydrate, sorbitol, propylene glycol,polydimethylsiloxanes Silicon oil, cyclomethicone, ethanol/SD Alcohol40, dimethicone copolyol, aluminum zirconium tetrachlorohydrex gly, andwater). The gel, which is less viscous than conventional electrode gel,is maintained in the chamber with a mesh of openings at the end wherethe device is to contact the patient's skin. The gel does not leak out,and it can be dispensed with a simple screw driven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient. Rather thanusing agar as the conducting medium, an electrode can instead be incontact with in a conducting solution such as 1-10% NaCl that alsocontacts an electrically conducting interface to the human tissue. Suchan interface is useful as it allows current to flow from the electrodeinto the tissue and supports the conducting medium, wherein the devicecan be completely sealed. Thus, the interface is material, interposedbetween the conducting medium and patient's skin, that allows theconducting medium (e.g., saline solution) to slowly leak through it,allowing current to flow to the skin. Several interfaces are disclosedas follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.Another example is the KM10T hydrogel from Katecho Inc., 4020 GannettAve., Des Moines Iowa 50321.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the electrode and conducting solutionin from the tissue, yet allow current to pass.

The electrode-base based stimulator in FIG. 1B shows two equivalentelectrodes 342, side-by-side, wherein electrical current would passthrough the two electrodes in opposite directions. Thus, the currentwill flow from one electrode, through the tissue and back through theother electrode, completing the circuit within the electrodes'conducting media that are separated from one another. An advantage ofusing two equivalent electrodes in this configuration is that thisdesign will increase the magnitude of the electric field gradientbetween them, which is crucial for exciting long, straight axons such asthe vagus nerve in the neck and other deep peripheral nerves.

A preferred embodiment of the electrode-based stimulator is shown inFIG. 3A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 3B. As shown, the stimulator 30 comprises two heads 31 anda body 32 that joins them. Each head 31 contains a stimulatingelectrode. The body of the stimulator 32 contains the electroniccomponents and battery (not shown) that are used to generate the signalsthat drive the electrodes, which are located behind the insulating board33 that is shown in FIG. 3B. However, in other embodiments of theinvention, the electronic components that generate the signals that areapplied to the electrodes may be separate, but connected to theelectrode head 31 using wires. Furthermore, other embodiments of theinvention may contain a single such head or more than two heads.

Heads of the stimulator 31 are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel 34 that also serves as an on/off switch. A light35 is illuminated when power is being supplied to the stimulator. Thus,in this embodiment of the invention, mechanical and electroniccomponents of the stimulator (impulse generator, control unit, and powersource) are compact, portable, and simple to operate. A cap 36 isprovided to cover each of the stimulator heads 31, to protect the devicewhen not in use, to avoid accidental stimulation, and to preventmaterial within the head from leaking or drying. However, forembodiments of the stimulator head in which the head is covered withMylar or some other high-dielectric material that can capacitivelycouple the signal to the skin, the Mylar may completely seal the gelwithin the stimulator head, thereby preventing exposure of the gel tothe outside. In that case, there would be no gel evaporation. Then, thecap 36 would be less advantageous because the head can be cleanedbetween stimulation sessions (e.g., with isopropyl alcohol) with nochance of contaminating the internal gel.

Construction of the stimulator head is shown in more detail in FIG. 4.In the embodiment shown in FIGS. 4A and 4B, the stimulator head containsan aperture screen, but in the embodiment shown in FIGS. 4C and 4D,there is no aperture screen. Referring now to the exploded view shown inFIG. 4A, the electrode head is assembled from a snap-on cap 41 thatserves as a tambour for a conducting membrane 42, an aperture screen 43,the head-cup 44, the electrode which is also a screw 45, and alead-mounting screw 46 that is inserted into the electrode 45. Theelectrode 45 seen in each stimulator head has the shape of a screw thatis flattened on its tip. Pointing of the tip would make the electrodemore of a point source, such that the above-mentioned equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditions.Completed assembly of the stimulator head is shown in FIG. 4B, whichalso shows how the head is attached to the body of the stimulator 47.

As examples, the conducting membrane 42 may be a sheet of Tecophlicmaterial from Lubrizol Corporation, 29400 Lakeland Boulevard, Wickliffe,Ohio 44092. The apertures may be open, or they may be plugged withconducting material, for example, KM10T hydrogel from Katecho Inc., 4020Gannett Ave., Des Moines Iowa 50321. If the apertures are so-plugged,the conducting membrane 42 becomes optional. The head-cup 44 is filledwith conducting material, for example, SIGNAGEL Electrode Gel fromParker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004. Thesnap-on cap 41, aperture screen 43, head-cup 44 and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 4, or it may be tubularor conical or have some other inner surface geomety that will affect theNeumann boundary conditions.

The alternate embodiment of the stimulator head that is shown in FIG. 4Calso contains a snap-on cap 41, a conducting membrane 42, the head-cup44, the electrode which is also a screw 45, and a lead-mounting screw 46that is inserted into the electrode 45. This alternate embodimentdiffers from the embodiment shown in FIGS. 4A and 4B in regard to themechanical support that is provided to the conducting membrane 42.Whereas the aperture screen had provided mechanical support to themembrane in the other embodiment, in the alternate embodiment areinforcing ring 40 is provided to the membrane. That reinforcement ringrests on non-conducting struts 49 that are placed in the head-cup 44,and a non-conducting strut-ring 48 is placed within notches in thestruts 49 to hold the struts in place. An advantage of the alternateembodiment is that without apertures, current flow is less restrictedthrough the conducting membrane 42. Furthermore, although the struts andstrut-ring are made of non-conducting material in this alternateembodiment, the design may be adapted to position additional electrodeor other conducting elements within the head-cup for other morespecialized configurations of the stimulator head, the inclusion ofwhich will influence the electric fields that are generated by thedevice. Completed assembly of the alternate stimulator head is shown inFIG. 4D, without showing attachment to the body of the stimulator, andwithout showing the insertion of the lead-mounting screw 46. In fact, itis also possible to insert a lead under the head of the electrode 45,and many other methods of attaching the electrode to thesignal-generating electronics of the stimulator are known in the art.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. FIGS. 5A and 5B respectivelyprovide top and bottom views of the outer surface of the electricalstimulator 50. FIG. 5C provides a bottom view of the stimulator 50,after sectioning along its long axis to reveal the inside of thestimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 1B), and thepower-level controller is attached to the control unit (330 in FIG. 1B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 1B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.1B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (352 in FIG. 1B) to each headcompartment 57. In addition, a non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another.

In a preferred embodiment, the magnetic stimulator coil 341 in FIG. 1Ahas a body that is similar to the electrode-based stimulator shown inFIG. 5C. To compare the electrode-based stimulator with the magneticstimulator, refer to FIG. 5D, which shows the magnetic stimulator 530sectioned along its long axis to reveal its inner structure. Asdescribed below, it reduces the volume of conducting material that mustsurround a toroidal coil, by using two toroids, side-by-side, andpassing electrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 1A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 1A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 1A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (No. 4, April 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 1A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance. The currents passing throughthe coils of the magnetic stimulator will saturate the core (e.g., 0.1to 2 Tesla magnetic field strength for Supermendur core material). Thiswill require approximately 0.5 to 20 amperes of current being passedthrough each coil, typically 2 amperes, with voltages across each coilof 10 to 100 volts. The current is passed through the coils in bursts ofpulses, as described in connection with FIG. 2. Additional disclosure ofthe magnetic stimulator shown in FIG. 1A is provided in Applicant'scommonly assigned co-pending U.S. patent application Ser. No. 12/964,050entitled Magnetic Stimulation Devices and Methods of Therapy, to SIMONet al., which is hereby incorporated by reference for all purposes.

In preferred embodiments of the electrode-based stimulator shown in FIG.1B, electrodes are made of a metal, such as stainless steel. However, inother embodiments, the electrodes may have many other sizes and shapes,and they may be made of other materials [Thierry KELLER and AndreasKuhn. Electrodes for transcutaneous (surface) electrical stimulation.Journal of Automatic Control, University of Belgrade, 18(2, 2008):35-45;G. M. LYONS, G. E. Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace.An investigation of the effect of electrode size and electrode locationon comfort during stimulation of the gastrocnemius muscle. MedicalEngineering & Physics 26 (2004) 873-878; Bonnie J. FORRESTER and JerroldS. Petrofsky. Effect of Electrode Size, Shape, and Placement DuringElectrical Stimulation. The Journal of Applied Research 4, (2, 2004):346-354; Gad ALON, Gideon Kantor and Henry S. Ho. Effects of ElectrodeSize on Basic Excitatory Responses and on Selected Stimulus Parameters.Journal of Orthopaedic and Sports Physical Therapy. 20(1, 1994):29-35].

For example, there may be more than two electrodes; the electrodes maycomprise multiple concentric rings; and the electrodes may bedisc-shaped or have a non-planar geometry. They may be made of othermetals or resistive materials such as silicon-rubber impregnated withcarbon that have different conductive properties [Stuart F. COGAN.Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng.2008. 10:275-309; Michael F. NOLAN. Conductive differences in electrodesused with transcutaneous electrical nerve stimulation devices. PhysicalTherapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 3 to 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 3to 5 provide a uniform surface current density, which would otherwise bea potential advantage of electrode arrays, and which is a trait that isnot shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71(1999): 4944-4950]. Infact, patients found the design shown in FIGS. 3 to 5 to be less painfulin a direct comparison with a commercially available grid-patternelectrode [UltraStim grid-pattern electrode, Axelggard ManufacturingCompany, 520 Industrial Way, Fallbrook Calif., 2011].

The electrode-based stimulator designs shown in FIGS. 3 to 5 situate theelectrode remotely from the surface of the skin within a chamber, withconducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No.4,182,346, and U.S. Pat. No. 3,973,557, entitled Electrode, to Allisonet al; U.S. Pat. No. 4,215,696, entitled Biomedical electrode withpressurized skin contact, to Bremer et al; and U.S. Pat. No. 4,166,457,entitled Fluid self-sealing bioelectrode, to Jacobsen et al.] Thestimulator designs shown in FIGS. 3 to 5 are also self-contained units,housing the electrodes, signal electronics, and power supply. Portablestimulators are also known in the art, for example, patent U.S. Pat. No.7,171,266, entitled Electro-acupuncture device with stimulationelectrode assembly, to Gruzdowich. Novelty of the designs shown in FIGS.3 to 5 is not per se that the electrode is situated remotely from theskin with intervening conductive material, or that the devices areportable, but rather that two or more remote electrodes are configuredfor placement relative to the axis of a deep, long nerve, such that thestimulator along with a correspondingly suitable stimulation waveformshapes the electric field, producing a selective physiological responseby stimulating that nerve, but avoiding substantial stimulation ofnerves and tissue other than the target nerve, particularly avoiding thestimulation of nerves that produce pain.

Examples in the remaining disclosure will be directed to methods forusing the disclosed electrical stimulation devices for treating apatient. Selected nerve fibers are stimulated in different embodimentsof methods that make use of the disclosed electrical stimulationdevices, including stimulation of the vagus nerve at a location in thepatient's neck. At that location, the vagus nerve is situated within thecarotid sheath, near the carotid artery and the interior jugular vein.The carotid sheath is located at the lateral boundary of theretopharyngeal space on each side of the neck and deep to thesternocleidomastoid muscle. The left vagus nerve is sometimes selectedfor stimulation because stimulation of the right vagus nerve may produceundesired effects on the heart, but depending on the application, theright vagus nerve or both right and left vagus nerves may be stimulatedinstead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3 to 5 to stimulatethe vagus nerve at that location in the neck, in which the stimulatordevice 50 in FIG. 5 is shown to be applied to the target location on thepatient's neck as described above. The illustration would also apply tothe application of the magnetic stimulator device 530 in FIG. 5D. Forreference, locations of the following vertebrae are also shown: firstcervical vertebra 71, the fifth cervical vertebra 75, the sixth cervicalvertebra 76, and the seventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin. The vagusnerve 60 is identified in FIG. 7, along with the carotid sheath 61 thatis identified there in bold peripheral outline. The carotid sheathencloses not only the vagus nerve, but also the internal jugular vein 62and the common carotid artery 63. Features that may be identified nearthe surface of the neck include the external jugular vein 64 and thesternocleidomastoid muscle 65. Additional organs in the vicinity of thevagus nerve include the trachea 66, thyroid gland 67, esophagus 68,scalenus anterior muscle 69, and scalenus medius muscle 70. The sixthcervical vertebra 76 is also shown in FIG. 7, with bony structureindicated by hatching marks.

If it is desired to maintain a constant intensity of stimulation in thevicinity of the vagus nerve (or any other nerve or tissue that is beingstimulated), methods may also be employed to modulate the power of thestimulator in order to compensate for patient motion or other mechanismsthat would otherwise give rise to variability in the intensity ofstimulation. In the case of stimulation of the vagus nerve, suchvariability may be attributable to the patient's breathing, which mayinvolve contraction and associated change in geometry of thesternocleidomastoid muscle that is situated close to the vagus nerve(identified as 65 in FIG. 7). Methods for compensating for motion andother confounding factors were disclosed by the present applicant incommonly assigned co-pending application Ser. No. 12/859,568, entitledNon-Invasive Treatment of Bronchial Constriction, to SIMON, which ishereby incorporated by reference.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical or magnetic stimulationdevices that are disclosed herein. The position and angular orientationof the device are adjusted about that location until the patientperceives stimulation when current is passed through the stimulatorelectrodes. The applied current is increased gradually, first to a levelwherein the patient feels sensation from the stimulation. The power isthen increased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient. Stimulationparameters for each patient are adjusted on an individualized basis.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a time-varying sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. For example, thehypothalamus is well known to be responsive to the presence of brightlight, so exposing the patient to bright light that is fluctuating withthe same stimulation frequency as the vagus nerve (or a multiple of thatfrequency) may be performed in an attempt to enhance the role of thehypothalamus in producing the desired therapeutic effect. For migraineheadaches, the desired effect is to reduce the frequency of migrainesand/or the reduction of migraine pain and its duration [D. J. ANDERSON.The Treatment of Migraine with Variable Frequency Photo-Stimulation.Headache 29(1989):154-155; David NOTON. Migraine and photic stimulation:report on a survey of migraineurs using fickering light therapy.Complementary Therapies in Nursing and Midwifery 6(2000): 138-142]. Suchpaired stimulation does not rely upon neuronal plasticity and is in thatsense different from other reports of paired stimulation [Navzer D.ENGINEER, Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A.Shetake, Sindhu P. Sudanagunta, Michael S. Borland and Michael P.Kilgard. Reversing pathological neural activity using targetedplasticity. Nature (2011): published online doi:10.1038/nature09656].

Use of the above-described devices and methods to treat migraineheadaches is now disclosed. Migraine headache is a disorder of the braincharacterized by a complex, but stereotypical, dysfunction of sensoryprocessing. The annual prevalence of migraine is 6-9% among men and15-17% among women. Migraine appears in all ages but reaches a peak inmiddle age, decreasing in old age. Migraine headaches often occur onboth sides of the head in children, but then an adult pattern ofunilateral pain often emerges in adolescence. Migraine headache pain isusually located in the temple, forehead or eye, or back of the head,sometimes reported as starting in the occipital/neck regions, and laterbecoming fronto-temporal. The pain is throbbing and aggravated byphysical effort. Approximately 20-30% of migraine sufferers(migraineurs) experience an aura, ordinarily a visual aura. The auratypically lasts for 5 minutes to an hour, during which time the patientexperiences sensations such as moving zig-zag flashes of light, blindspots or tingling in the hand or face. Allodynia (perception of painwhen a usually nonpainful stimulus is applied, such as hair combing) isreported in about two-thirds of migraineurs during the attack [SCHER AI, Stewart W F, Ricci J A, Lipton R B. Factors associated with the onsetand remission of chronic daily headache in a population-based study.Pain. 106(2003):81-89; Bert B. VARGAS, David W. Dodick. The Face ofChronic Migraine: Epidemiology, Demographics, and Treatment Strategies.Neurol Clin 27 (2009): 467-479].

Both twin studies and population-based epidemiological surveys stronglysuggest that migraine without aura is a multifactorial disorder, causedby a combination of genetic and environmental factors. Inheritedsusceptibility for common migraine (without or with aura) involves agene sequence variant on chromosome 8, which is flanked between twogenes (PGCP and MTDH/AEG-1) that are involved in glutamate homeostasis.MTDH/AEG-1 regulates the activity of the EAAT2 gene product, which isresponsible for clearing glutamate from brain synapses in the brain.Plasma glutamate carboxypeptidase (PGCP) is a proteinase that acts onthe unsubstituted N- and C-termini of dipeptides, which like otherglutamate carboxypeptidases may regulate the concentration of glutamatein the extra cellular space.

Migraine with aura has an even stronger genetic basis. Families withFamilial Hemiplegic Migraine (FHM) most often have a mutation involvinga Cav2.1 (P/Q) type voltage-gated calcium channel on chromosome 19. Inother families with FMH, a mutation occurs on chromosome 1 in a geneencoding the A2 subunit of the Na+,K+ ATPase. A third mutant gene thatis located on chromosome 2, a neuronal voltage-gated sodium channel, hasalso been found to produce FMH.

Some migraine sufferers become symptom-free for long periods of time.Others continue to have headaches with fewer or less typical migrainefeatures, resembling tension-type headaches, rather than full-blownmigraine. Considering the above-mentioned age-related incidence ofmigraine, this may be partly due to aging. It may also be due to themigraineur learning to avoid the factors that trigger migraines or tosuccessful prophylactic treatment [SCHER A I, Stewart W F, Ricci J A,Lipton R B. Factors associated with the onset and remission of chronicdaily headache in a population-based study. Pain 106(2003):81-89;BOARDMAN H F, Thomas E, Millson D S, Croft P R. The natural history ofheadache: predictors of onset and recovery Cephalalgia26(2006):1080-1088; BIGAL M E, Lipton R B. Modifiable risk factors formigraine progression. Headache 46(9, 2006):1334-43; BIGAL M E, Lipton RB. Modifiable risk factors for migraine progression (or for chronicdaily headaches)—clinical lessons. Headache 46 (Suppl 3, 2006):S144-6].

Migraine attacks may also continue over many years without major changesin frequency, severity or symptoms. In some migraineurs, migraine attackfrequency and disability may increase over time, in which there may be aprogression from episodic migraine to chronic (chronified ortransformed) migraine. The progression may be due to treatmentexacerbating the problem, to unsuccessful or futile avoidance oftriggers, or conceivably to progressive neurological changes that areanalogous to progressive neurodegeneration [Paul R. MARTIN and ColinMacLeod. Behavioral management of headache triggers: Avoidance oftriggers is an inadequate strategy. Clinical Psychology Review 29 (2009)483-495]. Attempts have been made to document progressive neurologicalchanges in migraineurs so as better understand putative progression[VALFRE W, Rainero I, Bergui M, Pinessi L. Voxel-based morphometryreveals grey matter abnormalities in migraine Headache 48(2008):109-17].However, conclusions drawn from brain imaging of migraineurs iscontroversial because observed progressive changes might not beirreversible [Arne May. Morphing voxels: the hype around structuralimaging of headache patients. Brain 132(2009): 1419-1425]. Such imagingmay be most useful in conjunction with biomarkers that do not involvebrain imaging, but that may be also be used to diagnose, stage, andevaluate therapies for migraine [Aron D Mosnaim, Javier Puente andMarion E Wolf. Biological correlates of migraine and cluster headaches:an overview of their potential use in diagnosis and treatment. Pragmaticand Observational Research 1(2010): 25-32].

The diagnosis and treatment of migraine is complicated by the potentialco-morbidity of migraine with other disorders. Those disorders includeischemic stroke and transient ischemic attack (TIA), sub-clinicalcerebral lesions, coronary heart disease, patent foramen ovale,depression, generalized anxiety disorder, panic disorder, bipolardisorders, restless leg syndrome, obesity, epilepsy (co-morbid withaura), fibromyalgia, irritable bowel syndrome, and celiac disease.Additional disorders that may be co-morbid with migraine compriseallergic rhinitis, sinusitis, and asthma, the co-morbidity of which islargely responsible for the considerable underreporting and misdiagnosisof migraine [H. C. DIENER, M. Küper, and T. Kurth. Migraine-associatedrisks and co-morbidity. J Neurol (2008) 255:1290-1301; Shuu-Jiun WANG,Ping-Kun Chen and Jong-Ling Fuh. Co-morbidities of migraine. Frontiersin Neurology 1 (Article 16, 2010): pp. 1-9. doi:10.3389/fneur.2010.00016; Marcelo E. BIGAL, Richard B. Lipton, Philip R.Holland, Peter J. Goadsby. Obesity, migraine, and chronic migraine.Possible mechanisms of interaction. Neurology 68 (2007): 1851-1861].

A migraine headache typically passes through the following stages:prodrome, aura, headache pain, and postdrome. All these phases do notnecessarily occur, and there is not necessarily a distinct onset or endof each stage, with the possible exception of the aura. An interictalperiod follows the postdrome, unless the postrome of one migraine attackoverlaps the prodrome of the next migraine attack.

The prodrome stage comprises triggering events followed by premonitorysymptoms. Triggers (also called precipitating factors) usually precedethe attack by less than 48 h. The most commonly reported triggers are:stress and negative emotions; hormonal factors for females(menstruation, menopause, pregnancy, use of oral contraceptives, andhormone replacement therapy); flicker, glare and eyestrain; noise; odors(exhaust fumes, cleaning solutions, perfume); hunger and thirst (skippedmeals, delayed meals, fasting, dehydration, withdrawal of reactive foodsand drinks, particularly caffeinated); consumption of certain foods(e.g., chocolate, monosodium glutamate, pungent foods) and alcohol;weather (cold, heat, high humidity, sudden changes in weather, allergenssuch as pollen); fatigue; and lack of sleep or too much sleep [BursteinR, Jakubowski M. A unitary hypothesis for multiple triggers of the painand strain of migraine. J Comp Neurol 493(2005):9-14; Vincent T. Martin,Michael M. Behbehani. Towards a rational understanding of migrainetrigger factors. Medical Clinics of North America 85(4, 2001): 911-41].

The prodrome is often characterized by fatigue, sleepiness, elation,food cravings, depression, irritability, among other symptoms. Clinicalsigns of sensory hyper-excitability often make their debut during thepremonitory phase, which later accompany the headache phase, such asphoto/phonophobia, hyperosmia and cutaneous allodynia of the scalp.Patients may also describe nausea during the prodrome. The averageduration of the prodrome is 6 to 10 hours, but in half of migraineattacks, the prodrome is less than two hours (or absent), and inapproximately 15% of migraine attacks, the prodrome lasts for 12 hoursto 2 days. The following symptoms were found to be most predictive ofimminent headache pain: difficulty with speech, reading or writing, andyawning. Many prodromal symptoms persist after the headache (during thepostdrome), but the following decrease significantly: yawning, blurredvision, and nausea/vomiting [Leslie KELMAN. The premonitory symptoms(prodrome): a tertiary care study of 893 migraineurs. Headache 44(2004):865-872; N. J. Giffin, L. Ruggiero, R. B. Lipton, S. D. Silberstein, J.F. Tvedskov, J. Olesen, J. Altman, P. J. Goadsby, and A. Macrae.Premonitory symptoms in migraine. An electronic diary study. Neurology60 (2003):935-940].

It is widely agreed that the aura, which is present in 20-30% ofmigraine attacks, is due to cortical spreading depression (CSD) withinthe brain, as now described. An electrophysiological wave is usuallyinitiated within the occipital region of the brain where visualprocessing occurs, and the wave propagates at a rate of approximately 3mm/min through neighboring cortical tissue, which is perceived as ascintillating scotoma (zig-zag line) that moves within the visual fieldas the CSD propagates. Such an aura may be initiated, for example, byviewing a bright light (e.g., reflection of the sun) while the occipitalregion is in a hypersensitive state. More generally, CSD is triggeredwhen a minimum critical volume of brain tissue is simultaneouslydepolarized by an intense stimulus, such as concentrated KClapplication, direct electrical stimulation, trauma, ischemia orepileptic activity. However, aura symptoms, regardless of their form,vary to a great extent in duration and severity from patient to patient,and also within the same individual. This variation may be due to uniquepaths that the CSD wave follows in individual attacks as it propagatesthrough regions of the brain that have different functions (e.g.,related to speech, memory, motor functions). Furthermore, non-visual andpossibly non-perceived (silent) auras may also arise when the CSD is notinitiated in the occipital portion of the brain [C. AYATA. Spreadingdepression: from serendipity to targeted therapy in migraineprophylaxis. Cephalalgia 29 (2009), 1097-1114; Markus A. DAHLEM, FelixM. Schneider, and Eckehard Scholl. Failure of feedback as a putativecommon mechanism of spreading depolarizations in migraine and stroke.Chaos 18(2, 2008):026110, pp. 1-11; M B VINCENT and N Hadjikhani.Migraine aura and related phenomena: beyond scotomata andscintillations. Cephalagia 27 (12, 2007):1368-77].

Although the headache phase can begin at any hour, it most commonlybegins as mild pain when the patient awakens in the morning. It thengradually builds at variable rates to reach a peak at which the pain isusually described as moderate to severe. The typical headache isunilateral and throbbing, aggravated by movement, with all stimulitending to accentuate the headache. Patients frequently developcutaneous allodynia, and sensory hypersensitivity results in patientsseeking a dark, quiet place. Blurry vision, nasal stuffiness, anorexia,hunger, diarrhea, abdominal cramps, polyuria, facial pallor, sensationsof heat or cold, and sweating might also occur. Depression, fatigue,anxiety, nervousness, irritability, and impairment of concentration arecommon. The pain phase lasts 4-72 h in adults and 1-72 h in children,with a mean duration generally of less than 1 day. The pain intensityusually follows a smooth curve with a crescendo with a diminuendo.

After the headache has resolved, many patients are left with a postdromethat lingers for one to two days. The main complaints are cognitivedifficulties, such as mental tiredness. Patients also describe symptomsof neural hyperexcitability, such as photophobia and allodynia.

The following is known about the pathophysiology of migraine. Thetrigeminovascular system consists of the neurons innervating thecerebral vessels whose cell bodies are located in a trigeminal ganglion[Arne M A Y and Peter J Goadsby. The Trigeminovascular System in Humans:Pathophysiologic Implications for Primary Headache Syndromes of theNeural Influences on the Cerebral Circulation. Journal of Cerebral BloodFlow and Metabolism 19(1999): 115-127]. It is widely accepted thatmigraine is a neurovascular disorder, wherein the intracranial throbbingpain of migraine is mediated by the interaction between nerves and bloodvessels, involving neuronal activity and inflammation along thetrigeminovascular pathway [Daniela PIETROBON and Jörg Striessnig.Neurobiology of migraine. Nature Reviews Neuroscience 4 (2003): 386-398;Stephen D SILBERSTEIN. Migraine. LANCET 363 (2004):381-391; M. LINDE.Migraine: a review and future directions for treatment. Acta NeurolScand 114(2006): 71-83; Egilius L. H. SPIERLINGS. Mechanism of migraineand action of antimigraine medications. Medical Clinics of North America85 (4, 2001): 943-958; Peter J. GOADSBY, Richard B. Lipton, Michel D.Ferrari. Migraine—Current understanding and treatment. N Engl J Med 346(4, 2002): 257-270; Peter J. GOADSBY. Migraine pathophysiology. Headache45[Suppl 1, 2005]:S14-S24; R J HARGREAVES and S L Shepheard.Pathophysiology of Migraine—New Insights. Can. J. Neurol. Sci. 26(Suppl. 3, 1999): S12-S19; Daniela PIETROBON. Migraine: New molecularmechanisms. Neuroscientist 11(4, 2005): 373-386; Curtis P. SCHREIBER.The pathophysiology of primary headache. Prim Care Clin Office Pract 31(2004) 261-276; Carlos M. VILLALON, David Centurión, Luis FelipeValdivia, Peter de Vries and Pramod R. Saxena. Migraine:Pathophysiology, Pharmacology, Treatment and Future Trends. CurrentVascular Pharmacology 1 (2003): 71-84; GOADSBY P J, Charbit A R, AndreouA P, et al. Neurobiology of migraine. Neuroscience 2009; 161:327-341;Till SPRENGER and Peter J Goadsby. Migraine pathogenesis and state ofpharmacological treatment options. BMC Medicine 7(2009):71,doi:10.1186/1741-7015-7-71, pp 1-5].

The cranial blood vessels are illustrated in FIG. 8. As seen in FIG. 8A,the cranial vessels (arteries and veins) 830 lie between the skullcapbone 810 and grey matter of the cerebral hemispheres 841, within themeninges that comprises the dura mater 820, the arachnoid mater 822 andthe pia mater 840. Other structures shown in FIG. 8A include skin 801,connective tissue 802, aponeurosis 803, loose areolar tissue 804,pericranium 805, subdural space 821, subarachnoid space 823, superiorsagittal sinus 824, and an arachnoid granulation 825. The cranialvessels 830 are shown here within the dura mater 820. However, it isunderstood in what follows that the relevant noiceceptive nerve fibersmay be located not only around the large cranial vessels, but alsoaround pial vessels, sinuses such as the superior sagittal sinus 824,and dura mater 820.

The trigeminal ganglion is a sensory ganglion of the trigeminal nerve.The trigeminal nerve (V cranial nerve) consists of three main branches,the ophthalmic (V1), maxillary (V2), and mandibular (V3), each providingsomatosensory innervations of distinct regions of the head, face, andorofacial cavity. Although the migraine headache pain arises primarilyfrom activation of the opthalmic branch (V1), all branches of thetrigeminal nerve share the same basic pathophysiology. For manyindividuals the first symptom of altered trigeminal function withsubsequent inflammatory protein release may be at the maxillary (V2) oreven mandibular (V3) trigeminal divisions. This is important clinicallybecause some patients may experience the first symptoms in the regioninnervated by V2, namely, the area of the nasal passages, and they maybe misdiagnosed (through the patient's own self diagnosis or clinician'sdiagnosis) with sinus headache. However, a trigeminally mediatedneuroinflammatory response at the level of the nasal passages canexplain the nasal congestion, discharge, and discomfort experienced bymany patients at the onset of their migraine attacks. Similarly,pericranial (jaw and neck) muscle tenderness is a common symptom inmigraine, which might be attributed in part to activation of themandibular (V3) trigeminal division.

As shown in FIG. 8B, the development of headache depends on theactivation of nociceptive afferent fibers 860 of trigeminal ganglionneurons innervating the blood vessels 830 in the meninges. Activation ofthe trigeminovascular afferents 860 by a variety of mechanisms leads tothe release of vasoactive neuropeptides in the meninges. Thesetrigeminal fibers contain substance P (SP) and calcitonin gene-relatedpeptide (CGRP), both of which can be released when the fibers arestimulated. Neurokinin A (formerly known as substance K), produced fromthe same gene as substance P, may also be released. Trigeminal ganglionfiber stimulation also increases cerebral blood flow through release ofa powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP).Vasodilation of meningeal blood vessels also occurs via activation ofparasympathetic efferents 861, wherein nitric oxide (NO) andacetylcholine (ACh) are released. The dilation also causes mechanicalstretching or bending of the perivascular nerve fibers, which results infiber depolarization, in addition to that attributable to theabove-mentioned released chemicals.

Stimulation may also results in leakage of plasma from dural bloodvessels (plasma extravasation), leaked components of which maycontribute to the nociception. Additional structural changes in the duramater after trigeminal ganglion stimulation include degranulation ofmast cells 870 (not drawn to scale) and activation of macrophages 871(not drawn to scale). Activation of such resident immune cells, whichare prominent components of the intracranial meninges, is also likely toserve as an important step in promoting the enhanced excitability ofmeningeal nociceptors. Inhibition of neuroinflammation in the vicinityof a nociceptor might therefore be accomplished through the inhibitionof pro-inflammatory cytokines and/or histamine or the release ofanti-inflammatory cytokines and/or antihistamines.

In addition to the above-mentioned self-reinforcing mechanisms foractivation of nociceptive afferent fibers 860 of trigeminal ganglionneurons innervating the blood vessels 830 in the meninges, corticalspreading depression (CSD) that accompanies migraine aura may alsoactivate the fibers. FIG. 8A shows a wave of cortical spreadingdepression 850 that is propagating (shown with arrows) within thecerebral hemisphere. As seen in FIG. 8B, the wave may eventually reachpia mater 840, activating perivascular trigeminal terminals therein.Such CSD-mediated activation will stimulate nearby nociceptive fibersthat impinge upon a blood vessel 830, resulting in the release ofsubstance P, calcitonin gene-related peptide, etc.; and it will alsoresult in a nociceptive afferent signal that is sent to central brainstructures via the trigeminal nerve branch.

After meningeal stimulation and/or inflammation, the correspondingafferent signal 860 is relayed to the trigeminal nucleus caudalis (TNC),as shown in FIG. 9. As described above in connection with description ofthe branches of the trigeminal nerve, the meningeal signal arrives fromthe ophthalmic branch (V1), but more generally a signal may arrive fromthe maxillary (V2) and/or mandibular (V3) branches as well, which arealso labeled as an afferent signal 860. Stimulation of the superiorsagittal sinus (824 in FIG. 8) also causes excitation in the TNC, aswell as in the dorsal horn at the C1 and C2 levels. Stimulation of abranch of C2, the greater occipital nerve, increases neuronal activityin the same regions, i.e., the TNC and C1/2 dorsal horn. This group ofneurons from the superficial laminae of trigeminal nucleus caudalis andC1/2 dorsal horns is known functionally as the trigeminocervicalcomplex. Thus, a substantial portion of the trigeminovascularnociceptive signals comes through mostly caudal cells. This provides ananatomical explanation for the experience of pain to the back of thehead in migraine.

As also shown in FIG. 9, following neuronal transmission in the caudalbrain stem and high cervical spinal cord of the trigeminocervicalcomplex, information is relayed to the thalamus, contralateral to theacute migraine pain, which processes and forwards the processed signalto the cerebral cortex, where it is perceived as migraine pain.Stimulating the superior sagittal sinus (824 in FIG. 8) also activatesneurons in the ventrolateral periaqueductal gray matter (PAG) and in thedorsal pons, near the locus ceruleus. Notably, electrical stimulationwith electrodes in the PAG and locus ceruleus induces migraine-likeheadaches. The PAG is involved in craniovascular pain not only throughascending projections to the thalamus but also through descending,mostly inhibitory modulation of nociceptive afferent information viaprojections to serotonergic neurons in the raphe nucleus. Uponactivation, the nucleus locus ceruleus, the main central noradrenergicnucleus, reduces cerebral blood flow, apparently by causing vasodilationin other vessels to divert the flow of blood. In contrast, the mainserotonin-containing nucleus in the brain stem, the raphe nucleus,increases cerebral blood flow when activated.

As also shown in FIG. 9, a migraine-related pathway involves pre- andpostganglionic parasympathetic neurons in the superior salivatorynucleus (SSN) and sphenopalatine ganglion (SPG), respectively. The SSNstimulates the release of acetylcholine, vasopressin intestinal peptide,and nitric oxide from meningeal terminals of SPG neurons, resultingdirectly or indirectly in the cascade of events that include thedilation of intracranial blood vessels, plasma protein extravasation,and local release of inflammatory molecules that activate adjacentterminals of meningeal nociceptors. This autonomic activation also leadsto lacrimation, reddening of the eye, and nasal congestion. The efferentcircuit element 861 shown in FIG. 9 is the same as the elementso-labeled in FIG. 8B. The SSN receives extensive input from more thanfifty brain areas, three of which are shown in FIG. 9. Furthermore, thesame hypothalamic, limbic, and cortical areas that project to the SSNalso appear to receive extensive afferent connections from thetrigeminovascular pathway. This provides a neuroanatomical mechanism bywhich stimulation of the afferent 860 in FIGS. 8 and 9 can lead to apositive-feedback stimulation of the efferent 861 [BURSTEIN R,Jakubowski M. A unitary hypothesis for multiple triggers of the pain andstrain of migraine. J Comp Neurol 2005; 493:9-14].

The foregoing sequence of activation, from meninges inflammation totrigeminal nucleus caudalis to thalamus, PAG, locus ceruleus, raphenuclei and back via the SSN and SPG does not ascribe a proximal cause ofthe trigeminal activation, other than possibly the cortical spreadingdepression that is associated with aura experienced by some migraineurs.This is because the proximal events leading to activation of thetrigeminal ganglia fibers may trigger the migraine, but they are notnecessarily the cause of the migraine, for the following reason. Oncethe migraine has started, it becomes self-perpetuating, which is to say,painful stimulation from the ongoing migraine itself may be sufficientto feed back and maintain activation of the trigeminal ganglia, longafter the triggering events have passed. In fact, it is conceivable thatinternal random or chaotic fluctuations of neuronal activity within thetrigeminal ganglia itself, and the structures with which it isphysiologically connected, may be sufficiently amplified by positivefeedback of the system to trigger the migraine, without even the needfor an external triggering event. For this reason, the pathophysiologyof migraine triggers is important not so much as it relates to theinitial events of the migraine attack, but rather as it relates to theorigins of the hypersensitivity of the trigeminovascular and otherneurological systems in migraineurs.

Hypersensitivity in migraine headaches, as well as the common migraineprodromal symptoms, may result from connection of the trigeminovascularpathway with an abnormal hypothalamus and/or limbic system, which inturn may be associated with imbalanced neurotransmitter levels. Suchconnections are shown in FIG. 9, many of which involve the hypothalamus,which is activated during a migraine attack [Marie Denuelle, NellyFabre, Pierre Payoux, Francois Chollet, Gilles Geraud. HypothalamicActivation in Spontaneous Migraine Attacks. Headache 47(2007):1418-1426]. Many migraine patients experience premonitoryautonomic and endocrine symptoms (sleep disturbances, changes ofwakefulness and alertness, as well as changes of appetite and thirst)that may well be attributed to primary hypothalamic dysfunction. Inparticular, the association of migraine with hormonal changes and thefact that migraine occurs most often in women may be attributed toinvolvement of the hypothalamus. The hypothalamus may also regulateactivity of the thalamus, periaqueductal gray, locus ceruleus,trigeminocervical complex, and cortical structures via its secretion oforexin. Furthermore, the hypothalamus plays an important role in controlof nociception, for example, involving the release of endogenous opioidpeptides, as described below [K B Alstadhaug. Migraine and thehypothalamus. Cephalalgia 29(2009): 809-817].

Connections of the trigeminovascular pathway to the limbic system viathe hypothalamus may also explain in part the hypersensitivity that isassociated with migraine headaches. The extended amygdala with itsconnections within the limbic system mediates long-lasting responsesduring sustained stress, which is the prodromal symptom most commonlyassociated with migraine. Such responses persist long after thetermination of stress, so migraine nociception may be enhanced as aconsequence of the connection of the trigeminovascular pathway to anactivated limbic system.

Hyperactivity of cranial parasympathetic nerves was mentioned above inconnection with the superior salivatory nucleus and superiorsphenopalatinate ganglion. Thus, parasympathetic symptoms such as facialflushing, lacrimation and nasal stuffiness may accompany migraineattacks. In contrast, sympathetic hypofunction appears to be associatedwith migraine. Even during headache-free periods, migraineurs havereduced sympathetic function, as compared with non-migraineurs. This isevidenced in migrainers by reduced norepinephrine levels, adrenergicreceptor super-sensitivity, orthostatic intolerance, decreased Valsalvamaneuver response, impaired isometric exercise and cold-pressorresponses and impaired pupillary control. These observations areconsistent with the view that prolonged stimulation of the sympatheticnervous system in migraineurs has depleted norepinephrine levels. Thisleads to an increase in the release of other sympatheticneurotransmitters, particularly dopamine, adenosine, neuropeptide Y,dynorphin, and prostaglandins. Nausea/vomiting and yawning are symptomsthat are associated with increased dopamine levels. Increased painsensitivity and inflammation are symptoms that are associated withincreased prostaglandin levels. Drowsiness is a symptom that isassociated with increased adenosine levels. Also, the decreasednorepinephrine levels will result in orthostatic intolerance andvasodilation. Furthermore, because the sympathetic system normally actsto inhibit the trigeminal system, hypofunction of the sympatheticnervous system will promote migraine attacks. The sympathetic nervoussystem works in conjunction with the hypothalamus and limbic system aspart of the physiological stress response system. Then, according tothis view, a prime cause of migraine would be prolonged stress and itssequela in a susceptible individual, which is consistent with the factthat stress is cited as the primary trigger migraine attacks. Theanticipation of migraine, as well as the actual migraine attacks, willcontribute to that stress [Stephen J. Peroutka. Migraine: a chronicsympathetic nervous system disorder. Headache 44(2004): 53-64].

In addition to its role in producing prodromal symptoms such as yawning,dopamine that is produced in the hypothalamus and elsewhere may also actdirectly on trigeminal afferents to modulate (generally inhibit) thetrigeminocervical complex [Annabelle R. CHARBIT, Simon Akerman and PeterJ. Goadsby. Dopamine: what's new in migraine? Current Opinion inNeurology 23 (2010):275-281]. Another neurotransmitter that isimplicated in migraine is serotonin (5-HT), wherein a low 5-HT statefacilitates activation of the trigeminovascular nociceptive pathway wheninduced by cortical spreading depression [E. HAMEL. Serotonin andmigraine: biology and clinical implications. Cephalalgia 27 (2007):1295-1300].

Current treatments for migraine are made in the context of itsabove-described pathophysiology, but are often based on trial and error.Pharmacological treatments may be divided into those that are intendedto prevent migraine attacks and those administered during an attack.Current preventive treatment includes the administration of one or moreof the following: beta-blockers (Propranolol, Metoprolol),anticonvulsants (Valproate, Topiramate, Gabapentin, lamotrigine),antidepressants (Amitriptyline, dosulepin, nortriptyline, Venlafaxine),calcium-channel blockers (Flunarizine, Verapamil), serotonin antagonists(Pizotifen, Methysergide), and dietary supplements (Riboflavin, CoenzymeQ10). Drugs that are administered during a migraine attack fall into twocategories: analgesics and nonsteroidal anti-inflammatory drugs (NSAIDS)that are not specific for migraine; and largely migraine-specific drugs(ergot-related compounds and triptans). The former group of drugsinclude: aspirin, paracetamol, Naproxen and ibuprofen. To counter nauseaduring the migraine attack, anti-emetics are often administered as well(domperidone, metoclopramide). Migraine-specific drugs are administeredwhen the non-specific drugs are ineffective. They include ergot-relatedDihydroergotamine as a nasal spray or injection, and triptans, which areserotonin 5-HT1B/1D receptor agonists: Sumatriptan, Zolmitriptan,Naratriptan, Rizatriptan, Eletriptan, Almotriptan, and Frovatriptan.Often a different triptan will be administered if the currentlyadministered triptan is ineffective for three migraine attacks. Triptanshave cardiovascular side effects and are contraindicated duringpregnancy and when a selective serotonin reuptake inhibitor (SSRI) isbeing administered. Furthermore, only 30-40% of migraineurs arepain-free two hours after the administration of triptans. Of those whodo respond, one in three will experience a migraine recurrence within 24hours.

In situations in which the above-mentioned standard drug treatments areineffective, the following experimental drug treatments have been tried:Botulinum Toxin Type A for prophylaxis (possibly blocking the localrelease of glutamate and substance P) and divalproex sodium, whichincreases the levels of inhibitory neurotransmitter gamma-aminobutyricacid (GABA). Additional drugs are under trial, notably CGRP1antagonists, glutamate receptor antagonists, transient receptorpotential vanilloid (TRPV1) receptor antagonists, nitric oxide synthesisinhibitors, and prostanoid receptor antagonists [Peter J Goadsby, TillSprenger. Current practice and future directions in the prevention andacute management of migraine. Lancet Neurol 9 (2010): 285-98; ElizabethW. Loder, Steven B. Graff-Radford, Timothy R. Smith. Migraine treatmentstrategies. The rationale for early intervention. 2003 National HeadacheFoundation 820 N. Orleans, Suite 217, Chicago, Ill. 60610-3132; StephenD. Silberstein. Preventive treatment of migraine. TRENDS inPharmacological Sciences 27 (8, 2006): 410-415; Teshamae S. Monteith andPeter J. Goadsby. Acute Migraine Therapy: New drugs and new approaches.Current Treatment Options in Neurology 13(2011):1-14].

Non-pharmacological treatments of migraine headaches have a long history[Peter J. KOEHLER and Christopher J. Boes. A history of non-drugtreatment in headache, particularly migraine. Brain 133(2010):2489-2500]. Behavioral therapy is sometimes used when the patient hasoverused drugs [Grazzi L, Andrasik F, D'Amico D, et al. Behavioral andpharmacologic treatment of transformed migraine with analgesic overuse:outcome at 3 years. Headache 42 (2002):483-90]. Non-invasive physicaltreatments for migraine include spinal manipulation, mobilization,massage, therapeutic touch, therapeutic exercise, cold packs, andelectrical modalities (including pulsating electromagnetic fields[PEMF], cranial electrotherapy, interferential therapy, transcutaneouselectrical nerve stimulation [TENS], and ultrasound), and differentcombinations of physical treatments [Brønfort G, Nilsson N, Haas M,Evans R L, Goldsmith C H, Assendelft W J J, Bouter L M. Non-invasivephysical treatments for chronic/recurrent headache. Cochrane Database ofSystematic Reviews 2004 (update 2009), Issue 3. Art. No.: CD001878. DOI:10.1002/14651858.CD001878.pub2]. Another noninvasive physical treatmentfor migraine is phototherapy [D. J. Anderson. The Treatment of Migrainewith Variable Frequency Photo-Stimulation. Headache 29(1989):154-155;David Noton. Migraine and photic stimulation: report on a survey ofmigraineurs using fickering light therapy. Complementary Therapies inNursing and Midwifery 6(2000): 138-142].

Acupuncture has slightly better outcomes and fewer adverse effects thanprophylactic drug treatment for migraine [M. Romoli, G. Allais, G.Airola, C. Benedetto. Ear acupuncture in the control of migraine pain:selecting the right acupoints by the “needle-contact test”. Neurol Sci26(2005):S158-S161; Gianni Allais, Marco Romoli, Sara Rolando, IlariaCastagnoli Gabellari, Chiara Benedetto. Ear acupuncture in unilateralmigraine pain. Neurol Sci 31 (Suppl 1, 2010):S185-S187; Linde K, AllaisG, Brinkhaus B, Manheimer E, Vickers A, White A R. Acupuncture formigraine prophylaxis. Cochrane Database of Systematic Reviews 2009,Issue 1. Art. No.: CD001218. DOI: 10.1002/14651858.CD001218.pub2].

Greater occipital nerve blockade and trigger point injections have alsobeen used to treat migraine [Maria Gabriella SARACCO, W. Valfre, M.Cavallini, M. Aguggia. Greater occipital nerve block in chronicmigraine. Neurol Sci 31 (Suppl 1, 2010):S179-S180; Bert B. Vargas, DavidW. Dodick. The Face of Chronic Migraine: Epidemiology, Demographics, andTreatment Strategies. Neurol Clin 27 (2009) 467-479; Ashkenazi A, MatroR, Shaw J W, et al. Greater occipital nerve block using localanesthetics alone or with triamcinolone for transformed migraine: arandomized comparative study. J Neurol Neurosurg Psychiatr79(2008):415-7].

Electrical stimulation with implanted electrodes has also been tried, inlieu of occipital or auriculotemporal nerve blockade [Charles A.Popeney, Kenneth M. Aló. Peripheral Neurostimulation for the Treatmentof Chronic, Disabling Transformed Migraine. Headache 43(2003):369-375;Thomas Simopoulos, Zahid Bajwa, George Lantz, Steve Lee, Rami Burstein.Implanted Auriculotemporal Nerve Stimulator for the Treatment ofRefractory Chronic Migraine. Headache 50(6, 2010):1064-1069; U.S. Pat.No. 6,735,475, entitled Fully implantable miniature neurostimulator forstimulation as a therapy for headache and/or facial pain, to Whitehurstet al.].

Surgical treatment of those nerves may also be undertaken, althoughsurgery has the disadvantage of irreversibility [Ivica Ducic, Emily C.Hartmann, Ethan E. Larson. Indications and Outcomes for SurgicalTreatment of Patients with Chronic Migraine Headaches Caused byOccipital Neuralgia. Plast. Reconstr. Surg. 123(2009): 1453-1461;Jeffrey E. Janis, Daniel A. Hatef, Ivica Ducic, Jamil Ahmad, CorinneWong, Ronald E. Hoxworth, Timothy Osborn. Anatomy of theAuriculotemporal Nerve: Variations in Its Relationship to theSuperficial Temporal Artery and Implications for the Treatment ofMigraine Headaches. Plast. Reconstr. Surg. 125(2010): 1422-1428].

In addition, magnetic stimulation just below the occipital bone has beenused to treat migraine [Richard B Lipton, David W Dodick, Stephen DSilberstein, Joel R Saper, Sheena K Aurora, Starr H Pearlman, Robert EFischell, Patricia L Ruppel, Peter J Goadsby. Single-pulse transcranialmagnetic stimulation for acute treatment of migraine with aura: arandomized, double-blind, parallel-group, sham-controlled trial. LancetNeurol 9(2010): 373-80; Thorsten Bartsch, Koen Paemeleire and Peter J.Goadsby. Neurostimulation approaches to primary headache disorders.Current Opinion in Neurology 22(2009):262-268; Peter J Goadsby, TillSprenger. Current practice and future directions in the prevention andacute management of migraine. Lancet Neurol 9(2010): 285-98].

Finally, vagal nerve stimulation (VNS) has been used to treat migraineheadaches. However, only invasive VNS has been reported; the VNS has notbeen reported to treat nasal congestion or other features resembling a“sinus” headache; and the parameters of stimulation are different thanthe parameters disclosed herein [R M SADLER, R A Purdy & S Rahey. Vagalnerve stimulation aborts migraine in patient with intractable epilepsy.Cephalalgia 22(2002), 482-484; E. Daniela HORD, M. Steven Evans, SajjadMueed, Bola Adamolekun, and Dean K. Naritoku. The Effect of Vagus NerveStimulation on Migraines. The Journal of Pain 4 (9, 2003): 530-534;Duncan A. GROVES, Verity J. Brown. Vagal nerve stimulation: a review ofits applications and potential mechanisms that mediate its clinicaleffects. Neuroscience and Biobehavioral Reviews 29 (2005) 493-500; AMAUSKOP. Vagus nerve stimulation relieves chronic refractory migraineand cluster headaches. Cephalalgia 25(2005):82-86; M E LENAERTS, K JOommen, J R Couch & V Skaggs. Can vagus nerve stimulation help migraine?Cephalalgia 28(2008), 392-395; Alberto Proietti CECCHINI, Eliana Mea andVincenzo Tullo, Marcella Curone, Angelo Franzini, Giovanni Broggi, MarioSavino, Gennaro Bussone, Massimo Leone. Vagus nerve stimulation indrug-resistant daily chronic migraine with depression: preliminary data.Neurol Sci 30 (Suppl 1, 2009):S101-S104; A. MAY and T. P. Jürgens.Therapeutic neuromodulation in primary headache syndromes(Therapeutische Neuromodulation bei primären Kopfschmerzsyndromen).Nervenarzt 2010: doi_(—)10.1007/s00115-010-3170-x; Patent applicationUS20050216070, entitled Method and system for providing therapy formigraine/chronic headache by providing electrical pulses to vagusnerve(s), to Boveja et al.].

When all the above methods of treating migraine fail, rescue treatmentinvolves the administration of opioids, which has as its primary sideeffect the possibility of addiction. Accordingly, the use of opiates isgenerally restricted to patients who are unresponsive to many differentmigraine-specific therapies and who require frequent emergency roomvisits to abort their migraine attacks. However, even daily opioids mayfail to provide sustained relief [Joel R. SAPER, Alvin E. Lake III,Philip A. Bain, Mark J. Stillman, John F. Rothrock, Ninan T. Mathew,Robert L. Hamel, Maureen Moriarty, Gretchen E. Tietjen. A Practice Guidefor Continuous Opioid Therapy for Refractory Daily Headache: PatientSelection, Physician Requirements, and Treatment Monitoring. Headache50(2010): 1175-1193].

It is possible to use drugs other than narcotics in an attempt todissociate the neural pathways associated with pain production frompathways involving the perception of pain. One such drug is ketamine,which is very commonly used as a dissociative anesthetic, especially inveterinary medicine. At certain doses, ketamine produces euphoria and istherefore consumed by drug abusers. When used to treat depression,ketamine produces effects much more quickly than conventionalantidepressant medication [Nancy A. Melville. Bolus Dose of KetamineOffers Fast-Acting Alleviation of Acute Depression in ED Setting.Medscape Medical News (2010): Article 729622; Carlos A. Zarate, JaskaranB. Singh, Paul J. Carlson, Nancy E. Brutsche, Rezvan Ameli, David A.Luckenbaugh, Dennis S. Charney, Husseini K. Manji. A Randomized Trial ofan N-methyl-D-aspartate Antagonist in Treatment-Resistant MajorDepression. Arch Gen Psychiatry. 2006; 63:856-864].

As described below, ketamine is also effective in the treatment ofmigraine headaches. The speed with which ketamine produces its effects,as well as the nature of those effects, are similar to those produced byApplicant's disclosed vagal nerve stimulation (VNS) methods, asdescribed also in commonly assigned co-pending patent application Ser.No. 13/024,727, entitled “Non-invasive methods and devices for inducingeuphoria in a patient and their therapeutic application,” which ishereby incorporated by reference. The neuronal mechanisms underlying theeffects of ketamine and the disclosed VNS methods appear to be similar,which leads to the present invention that uses the disclosed VNSstimulation to treat migraine. Because the disclosed VNS method has noknown side-effects, it may be more suitable than the use of ketamine andrelated compounds to treat migraine.

Ketamine is a glutamate receptor antagonist. NICOLODI et al. claim thatketamine (as well as the NMDA receptor antagonist gapapentin) can curechronic migraine by causing it to revert to episodic migraine [NICOLODIM, Sicuteri F. Negative modulators of excitatory amino acids in episodicand chronic migraine: preventing and reverting chronic migraine. Speciallecture 7th INWIN Congress. Int J Clin Pharmacol Res. 18(2, 1998):93-100]. Evidence has also been presented that ketamine can stopmigraine aura, at least in patients with familial hemiplegic migraine[KAUBE H, Herzog J, Käufer T, Dichgans M, Diener H C. Aura in somepatients with familial hemiplegic migraine can be stopped by intranasalketamine. Neurology 55(1, 2000): 139-41]. Several other glutamatereceptor antagonist drugs are under active development for the treatmentof migraine [MONTEITH T S, Goadsby P J. Acute migraine therapy: newdrugs and new approaches. Curr Treat Options Neurol. 2011 (1,2011):1-14]. Some of the mechanisms by which glutamate receptor agonistsinhibit migraine headaches involve the colocalization of glutamate with5-HT(1B/1D/1F) receptors in trigeminal ganglia, as well as the effectsof glutamate receptor agonists on the diameter of arteries that areinvolved in migraine pain [MA Q P. Co-localization of 5-HT(1B/1D/1F)receptors and glutamate in trigeminal ganglia in rats. Neuroreport 12(8,2001):1589-1591; CHAN K Y, Gupta S, de Vries R, Danser A H, Villalón CM, Muñoz-Islas E, Maassenvandenbrink A. Effects of ionotropic glutamatereceptor antagonists on rat dural artery diameter in an intravitalmicroscopy model. Br J Pharmacol. 160 (6, 2010):1316-25]. Furthermore,inherited forms of migraine susceptibility involve a sequence variant onchromosome 8q22.1, which is flanked by two genes involved in glutamatehomeostasis, leading to the view that disruption of glutamate metabolismis a primary cause of migraine, and that treatment of migraine shouldaddress that cause.

In a preferred embodiment of the invention, glutamate receptorantagonist effects, brought about by nerve stimulation, comprise thefollowing. The glutamate receptor, which is ordinarily found on thesurface of a post-synaptic cell, has an ion channel that only opens whenthe following two conditions are met simultaneously: glutamate is boundto the receptor, and the postsynaptic cell is depolarized (which removesMg2+ blocking the channel). To antagonize glutamate receptors, astimulated nerve may (1) block/inhibit the synthesis or release of theneurotransmitter glutamate from a pre-synaptic cell; (2) maintain apost-synaptic cell in a hyperpolarized state; (3) directly or indirectlymodulate activity of the receptor via control of endogenous modulatorssuch as glutathione, lipoic acid, H+, K+, and 5-HT1B/1D/1F receptors;and (4) a combination of these effects. The invention contemplates thatdifferent glutamate receptors (N-methyl-D-aspartate (NMDA),a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and kainate)may be modulated by such nerve stimulation.

Pathways relating Applicant's vagal nerve stimulation method to itsobserved effects in migraineurs, including rapid dissociation of theperception of pain from the production of pain (relief within seconds tominutes through a euphoria-like mechanism) are shown in FIG. 9. Pathwaysrelating to the relief of sinus congestion and related symptoms,involving for example direct or indirect inhibition of the superiorsalivatory nucleus parasympathetic pathway, are also shown. It isunderstood that the pathways shown there are a simplification of theactual mechanisms, that not all of the pathways may participate equally,that pathways not shown may also participate, and that futureinvestigations may require that the pathways be modified. The arrowsindicate the direction of information flow, some of which arebi-directional.

Beginning in the right middle side of FIG. 9, the vagus nerve isstimulated, and the resulting signal is sent towards the brain. Vagalafferents traverse the brainstem in the solitary tract, with some eightypercent of the terminating synapses being located in the nucleus of thetractus solitarius (NTS). The NTS projects to a wide variety ofstructures, as shown in FIG. 9, including the amygdala, the nucleusaccumbens, and the hypothalamus [JEAN A. The nucleus tractus solitarius:neuroanatomic, neurochemical and functional aspects. Arch Int PhysiolBiochim Biophys 1991; 99(5):A3-A52]. The NTS also projects to theparabrachial nucleus, which in turn projects to the hypothalamus, thethalamus, the amygdala, the anterior insular, and infralimbic cortex,lateral prefrontal cortex, and other cortical regions (only the thalamusprojection is shown in FIG. 9, from which the perception of pain mayreach the cortex). Other pathways from the NTS to many of the otherstructures shown in FIG. 9 are multi-synaptic [M. CASTLE, E. Comoli andA. D. Loewy. Autonomic brainstem nuclei are linked to the hippocampus.Neuroscience 134 (2005) 657-669]. Through its direct or indirectprojection to the amygdala and the nucleus accumbens, the NTS gainsaccess to amygdala-hippocampus-entorhinal cortex pathways of the limbicsystem. The disclosed method of vagal nerve stimulation uses parameters(intensity, pulse-width, frequency, duty cycle, etc.) that activate thelimbic system via the amygdala and nucleus accumbens or other routes[Jeong-Ho CHAE, Ziad Nahas, Mikhail Lomarev, Stewart Denslow, Jeffrey P.Lorberbaum, Daryl E. Bohning, Mark S. George. A review of functionalneuroimaging studies of vagus nerve stimulation (VNS). Journal ofPsychiatric Research 37 (2003) 443-455; G. C. Albert, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009) 1042-1060].

In its most basic conception, the limbic system can be defined by itsinput from dopaminergic neurons originating in the ventral tegmentalarea (VTA) of the brain. Those dopamine-producing neurons are shown inFIG. 9 as 81, projecting to the nucleus accumbens, with neuronsbranching nearby that project to the ventral palladium (VP) andprefrontal cortex (PFC). In addition, dopamine-producing neurons 81project from the VTA to the amygdala and to the hippocampus. The feelingof relief that may be felt by an individual is thought to occur when theVTA floods these dopaminergic neurons 81 with dopamine, therebystimulating the nucleus accumbens, VP, PFC, amygdala, and hippocampus.

Feedback from the above-mentioned structures to the VTA determines themagnitude of the dopamine levels, as well as the steady state thatobtained before the stimulation. The feedback loops involve neurons thatuse gamma-aminobutyric acid (GABA) as their neurotransmitter 82 as wellas neurons that use glutamate as their neurotransmitter 83. TheGABAminergic neurotransmission is generally inhibitory, while theglutamatergic neurotransmission is generally excitatory. As shown inFIG. 9, glutmatergic neurotransmission 83 occurs from the amygdala, PFCand hippocampus to the nucleus accumbens, as well as from the thalamusto the PFC. As also shown in FIG. 9, GABAminergic neurotransmission 82occurs from the VTA and VP to the thalamus, from the nucleus accumbensto the VTA and VP, as well as within the VTA, which has the effect ofinhibiting dopamine neurotransmission. The mechanism of inhibition isthat a GABA-A receptor on the dopaminergic neuron binds to GABA releasedfrom a GABAminergic neuron, which inhibits dopaminergicneurotransmission. However, the GABAminergic neuron may containmu-opioid and/or CB1 cannabinoid receptors on its surface. Mu opioidreceptors are presynaptic, and inhibit neurotransmitter release. Inparticular, they inhibit the release of the inhibitory neurotransmitterGABA, and thereby disinhibit the dopamine pathways, causing moredopamine to be released.

Through such mechanisms, opioids and cannabinoids can indirectlymodulate neurotransmission [Janice C. Froehlich. Opioid peptides.Alcohol health and research world. 132-136; Anupama Koneru, SreemantulaSatyanarayana and Shaik Rizwan. Endogenous Opioids: Their PhysiologicalRole and Receptors. Global Journal of Pharmacology, 3 (3, 2009):149-153; Julie LeMerrer, Jerome A. J. Becker, Katia Befort and BrigitteL. Kieffer. Reward Processing by the Opioid System in the Brain. PhysiolRev 89(2009): 1379-1412]. Receptors for opioids are shown in FIG. 8 witha fork or goal-post symbol (

), and the opioids that bind and activate them are shown with a solidsquare (□). Different types of opioid receptors that modulateneurotransmission are found throughout the brain, but significant onesfor present purposes are shown in FIG. 9 in the VTA, nucleus accumbens,VP, parabrachial nucleus, and NTS. Similar receptors for cannabinoidsexist throughout the brain (not shown). It is thought that withoutneuromodulation via the opioid and cannabinoid receptors, thedopaminergic limbic system may generate a feeling of “want”, but withthe additional receptor systems, a hedonic feeling of “like” (or reliefthrough euphoria) may be generated [Julie LeMerrier, Jerome A. J.Becker, Katia Befort, and Brigitte L. Kieffer. Reward Processing by theOpioid System in the Brain. Physiol Rev 89 (2009): 1379-1412; Kent C.Berridge and Morten L. Kringelbach. Affective neuroscience of pleasure:reward in humans and animals. Psychopharmacology 199 (2008):457-480;Susana PECINA, Kyle S. Smith, and Kent C. Berridge. Hedonic Hot Spots inthe Brain. Neuroscientist 12(6, 2006):500-511].

Endorphins are endogenous opioid peptides that function asneurotransmitters, and beta-endorphin is released into the brain fromhypothalamic neurons. It is also released into the blood from thepituitary gland under the control of the hypothalamus, but becauseendorphins cannot pass easily through the blood-brain barrier, only theopioids under direct control of the hypothalamus are shown with thesolid square (□) that is attached to the hypothalamus in FIG. 9. Theraphe nuclei also cause the release endorphins. Thus, through theproduction of endogenous opioid peptides, the hypothalamus and raphenuclei can modulate neurotransmission involving opioid receptors thatwere described above. The hypothalamus also connects bi-directionally tocomponents of the limbic system, through the medial forebrain bundle.Such bidirectional connections are shown in FIG. 9 to the amygdala,nucleus accumbens, and VTA with arrows on both ends. [Pedro RADA,Jessica R. Barsonb Sarah F. Leibowitz, Bartley G. Hoebel. Opioids in thehypothalamus control dopamine and acetylcholine levels in the nucleusaccumbens. Brain Research 1312(2010): 1-9].

According to the foregoing description of FIG. 9, many pathwayscollectively bring about the euphoria-like mechanism whereby migrainepain production is dissociated from the perception of migraine pain.From the NTS projections, direct inhibition of the nucleus accumbens andindirect inhibition via the amygdala may lead to a reduced GABAnergicsignal from the nucleus accummbens to the VTA and VP. Inhibition of thethalamus via the parabrachial nucleus reduces stimulation of theprefrontal cortex, which in turn results in reduced stimulation of thenucleus accumbens. From the NTS input to the hypothalamus, stimulationmay (1) produce endogenous opioids that can further inhibit GABAnergicinhibition through binding to the opioid receptors; and (2) directlystimulate the VTA and inhibit the amygdala and/or nucleus accumbens.

Such effects would bring about a significant dopaminergicneurotransmission disinhibition in the VTA, which responds by floodingthe nucleus accumbens, amygdala, VP, PFC and hippocampus with dopaminealong the dopaminergic projections 81, giving rise to the dissociation.Continued stimulation of the vagus nerve prevents neurotransmitterequilibrium from being restored, during which time gene expression andother biochemical effects alter the physiology of the nerve cells. Whenstimulation is terminated, the duration of the subsequent dissociationis a function of the time needed for neuronal changes, such asbiochemical effects and gene expression that were altered during thestimulation, to be restored to their former equilibria.

The nucleus tractus solitarius (NTS) also connects to structures thatwere identified above as being involved directly in the pathophysiologyof migraine. Those structures include the hypothalamus, periaqueducatalgray, locus ceruleus, and raphe nuclei. They are in turn connected toother structures that are more closely linked to the vascular afferents860 and efferents 861, which are respectively the trigeminocervicalcomplex and superior salivatory nucleus. The hypothalamus may alsoregulate activity of the thalamus, periaqueductal gray, locus ceruleus,trigeminocervical complex, and cortical structures via its secretion oforexin and other chemicals. Although the pathways from the NTS are shownin FIG. 9 to be unidirectional, it is understood that many of them arein fact bi-directional, such that the NTS receives and processes neuralinformation, rather than simply relaying signals from one place toanother

[JEAN A. The nucleus tractus solitarius: neuroanatomic, neurochemicaland functional aspects. Arch Int Physiol Biochim Biophys 1991;99(5):A3-A52]. The locus ceruleus is responsible for mediating many ofthe sympathetic effects during stress, including those associated withmigraine. The locus ceruleus is activated by stress, and will respond byincreasing norepinephrine secretion, which in turn will alter cognitivefunction through the prefrontal cortex, increase motivation throughnucleus accumbens, activate the hypothalamic-pituitary-adrenal axis, andincrease the sympathetic discharge/inhibit parasympathetic tone throughthe brainstem. Such inhibition of parasympathetic tone will specificallyinhibit the parasympathetic pathway via the superior salivatory nucleus,thereby blocking the positive feedback loop that contributes to themaintenance of migraine pain and thereby bringing about a reduction insinus congestion and related symptoms.

The disclosed vagal nerve stimulation may also aid in the prevention ofrecurrent migraine attacks over a longer period of time, through itseffects on the raphe nuclei and locus ceruleus. The raphe nuclei provideextremely widespread serotonergic innervation of the entire cortex,diencephalon, and other brain structures. The NTS projects to multipleraphe nuclei, as do other nuclei of the dorsal medullary vagal complex,but the complexity of NTS-raphe pathways and transmitters is greaterthan for NTS-locus ceruleus interactions. Thus, the locus ceruleus isthe major source of norepinephrine and the raphe of serotonin in most ofthe brain, and the NTS projects to both of them. Migraine is a diseasein which both norepinephrine and serotonin are chronically low, andstimulation of the locus ceruleus and raphe nuclei via the NTS mayameliorate that problem, at a minimum as a prophylactic [Stephen J.Peroutka. Migraine: a chronic sympathetic nervous system disorder.Headache 44(2004): 53-64; E. HAMEL. Serotonin and migraine: biology andclinical implications. Cephalalgia 27 (2007): 1295-1300].

The disclosed devices and methods may also be used to treat types ofheadaches that are co-morbid with migraine, or that overlap in symptomssuch that a diagnosis of migraine versus the other headache isdifficult. One such headache with potentially overlapping symptoms iscluster headache [A O Kaup, N T Mathew, C Levyman, J Kailasam, L AMeadors and S S Villarreal. ‘Side locked’ migraine and trigeminalautonomic cephalgias: evidence for clinical overlap. Cephalalgia23(2003): 43-49].

Cluster headache is a relatively rare but very painful disorderaffecting males more than females. Its attacks come in clusterstypically occurring 6 to 12 weeks at a time, anywhere from one to threetimes a year. The duration of a cluster headache 15 minutes to 3 hours,often beginning at night shortly after the patient has gone to sleep,and may recur two to six times during the night and into the next day.The pain is localized unilaterally in or around the eye, and almostinvariably, cluster headache is accompanied by autonomic symptoms suchas lacrimation, eye redness, drooping eyelid, nasal stuffiness, andrunny nose [Arne May. Cluster headache: pathogenesis, diagnosis, andmanagement. Lancet 366(2005): 843-55].

Anatomical structures identified in FIG. 9 in connection with migraineare also involved in cluster headaches, including the trigeminovascularsystem, but the key site for triggering the pain and controlling thecycling features of the headache is in the posterior hypothalamic greymatter region. The associated autonomic dysregulation might originatecentrally in association with the hypothalamic disturbance, or throughtrigeminal discharge, or through compression of pericarotid sympatheticfibers due to vasodilation or perivascular edema that is evoked byparasympathetic overactivity during attacks [Peter J Goadsby.Pathophysiology of cluster headache: a trigeminal autonomic cephalgia.Lancet Neurology 1(2002): 251-57; Massimo Leone, Gennaro Bussone.Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol8(2009): 755-64]. Trauma may also be involved in the pathogenesis ofcluster headaches [Russell W. Walker. Cluster Headache and Head Trauma:Is There an Association? Current Pain and Headache Reports11(2007):137-140].

Inhalation of pure oxygen via a non-rebreathing facial mask is effectiveat stopping cluster headache attacks, and it is used for treatment inconjunction with migraine treatments, including sumatriptan and oralergotamine. Because there is highly specific activation of thehypothalamic grey matter in cluster headache, deep brain stimulation(DBS) in the hypothalamus is used to treat refractory cases [A Mauskop.Vagus nerve stimulation relieves chronic refractory migraine and clusterheadaches.

Cephalalgia 25(2005):82-96; Robert Levy, Timothy R. Deer, and JaimieHenderson. Intracranial Neurostimulation for Pain Control: A Review.Pain Physician 13(2010):157-165]. Vagal nerve stimulation has also beenused in conjunction with DBS [Angelo Franzini, G. Messina, MassimoLeone, Alberto Proietti Cecchini, Giovanni Broggi and Gennaro Bussone.Feasibility of simultaneous vagal nerve and deep brain stimulation inchronic cluster headache: case report and considerations. Neurol Sci 30(Suppl 1, 2009):S137-S139]. The present invention differs from othernerve stimulation treatments for cluster headaches in that it may beperformed without DBS or invasive nerve stimulation, including usingmagnetic stimulation, and in that it involves modulation of glutamate orglutamate receptors (e.g., Pathways 83 in FIG. 9).

The disclosed devices and methods may also be used to treat otherdisorders that may be co-morbid with migraine, such as anxietydisorders, in which the nervous system may also be hyper-reactive and inwhich attacks may be triggered by some of the same factors that triggermigraine and asthma attacks.

The annual prevalence of anxiety disorders is eighteen percent in thegeneral population, divided among particular forms of anxiety disorders(panic disorder, agoraphobia without panic, specific phobia, socialphobia, generalized anxiety disorder, posttraumatic stress disorder,obsessive-compulsive disorder, separation anxiety disorder) [Ronald C.Kessler, Wai Tat Chiu, Olga Demler, Ellen E. Walters. Prevalence,Severity, and Comorbidity of 12-Month DSM-IV Disorders in the NationalComorbidity Survey Replication. Arch Gen Psychiatry 62(2005):617-627].

Compared to individuals without migraine, migraineurs are 3.7 to 6.6times more likely to be diagnosed with panic disorder, 5.7 times morelikely to suffer from generalized anxiety disorder, 5.1 times morelikely to suffer from obsessive-compulsive disorder, and 2.6 times morelikely to be diagnosed with a phobia [H. C. DIENER, M. Küper, and T.Kurth. Migraine-associated risks and co-morbidity. J Neurol (2008)255:1290-1301; Nathalie Jette, Scott Patten, Jeanne Williams, WernerBecker, Samuel Wiebe. Comorbidity of Migraine and PsychiatricDisorders—A National Population-Based Study. Headache 2008; 48:501-516;Shuu-Jiun WANG, Ping-Kun Chen and Jong-Ling Fuh. Co-morbidities ofmigraine. Frontiers in Neurology 1 (Article 16, 2010): pp. 1-9. doi:10.3389/fneur.2010.00016; Stephen D. Silberstein. Shared Mechanisms andComorbidities in Neurologic and Psychiatric Disorders. Headache41(Supplement s1, 2001): S11-S18].

The treatment of anxiety disorders is important in and of itself, but itis all the more important in migraineurs because co-morbid anxietydisorder is associated with a progression from episodic migraines tochronic migraines [Todd A. Smitherman, Jeanetta C. Rains, and Donald B.Penzien. Psychiatric Comorbidities and Migraine Chronification. CurrentPain and Headache Reports 13(2009):326-331]. It should be noted thatanxiety disorders are comorbid with asthma, in addition to migraine, andall three may involve triggers and hypersensitivity [Peter P. Roy-Byrne,Karina W. Davidson, Ronald C. Kessler, et al. Anxiety disorders andcomorbid medical illness. General Hospital Psychiatry 30 (2008) 208-225;Naomi M. Simon and Diana Fischmann. The implications of medical andpsychiatric comorbidity with panic disorder. J Clin Psychiatry66(Supplement 4, 2005): 8-15]. Some of the association between migraineand anxiety disorders occurs in individuals who suffer from vertigo,which may be considered to be a special type of disease entity with itsown pathophysiology [J M Furman, C D Balaban, R G Jacob, D A Marcus.Migraine-anxiety related dizziness (MARD): a new disorder? J NeurolNeurosurg Psychiatry 2005 76: 1-8; Naomi M. Simon and Diana Fischmann.The implications of medical and psychiatric comorbidity with panicdisorder. J Clin Psychiatry 66(Supplement 4, 2005): 8-15]. Part of theassociation between migraine and anxiety disorder may be also due to acommon genetic disposition, for example with genes related to serotoninand/or to dopamine being involved [Xenia Gonda, Zoltan Rihmer, GabriellaJuhasz, Terezia Zsombok, Gyorgy Bagdy. High anxiety and migraine areassociated with the s allele of the 5HTTLPR gene polymorphism.Psychiatry Research 149 (2007) 261-266; Stephen J. Peroutka, Susan C.Price, Tara L. Wilhoit, and Keith W. Jones. Comorbid Migraine with Aura,Anxiety, and Depression Is Associated with Dopamine D2 Receptor (DRD2)NcoI Alleles. Molecular Medicine 4(1998): 14-21]. More generally though,the association between migraine and anxiety disorder has beenattributed to three mechanisms: aberrant serotonergic (5-HT)functioning, medication overuse or drug abuse (e.g., long-term use of“Ecstasy”), and psychological mechanisms (fear of pain, fear ofanxiety-related sensations, i.e., anxiety sensitivity, and unwarrantedavoidance behaviors) [Todd A. Smitherman, Jeanetta C. Rains, and DonaldB. Penzien. Psychiatric Comorbidities and Migraine Chronification.Current Pain and Headache Reports 13(2009):326-331].

The particular anxiety disorder that is cited as being most consistentlyassociated with migraine is panic disorder, so in what follows,treatment of panic disorder will be specifically discussed, with theunderstanding that other anxiety disorders may be treated as well. Aswith migraine, panic disorder occurs preferentially in women, and itsprevalence increases in adolescence and decreases with old age. Likemigraine, panic disorder attacks are said to be triggered, and as inmigraine the most commonly reported antecedent trigger is negative orstressful life events. At the cellular level, the trigger for panicattacks is thought to involve changes in sodium [A. I. Molosh, P. L.Johnson, S. D. Fitz, J. A. DiMicco, J. P. Herman, and A. Shekhar.Changes in central sodium and not osmolarity or lactate inducepanic-like responses in a model of panic disorder.Neuropsychopharmacology 35(6, 2010): 1333-1347].

The neurological pathways that are involved in panic disorder compriseconnections between many of the structures shown in FIG. 9, namely, theamygdala interacting with the parabrachial nucleus, pariaqueductal gray,hippocampus, prefrontal cortex, locus ceruleus, and hypothalamus.Respiratory effects that may be associated with asthma co-morbidity areparticularly mediated by signals through the parabrachial nucleus. Aswith migraine, the panic attack is self-sustaining after beingtriggered, but the positive feedback loops appear to involve autonomicpathways (e.g., with increased heart rate, blood pressure andrespiration) and cognitive recognition (increased fear resulting fromrecognized increasing fear) to a greater extent than migraine [Peter PRoy-Byrne, Michelle G Craske, Murray B Stein. Panic disorder. Lancet368(2006): 1023-1032]. Unless a migraine attack is coincident with thepanic attack, the trigeminocervical complex and superior salivatorynucleus are not necessarily part of the positive feedback loop.

Currently, selective serotonin reuptake inhibitors (SSRIs) are thepreferred treatment for panic disorder, on the basis of many positiveplacebo-controlled, randomized trials supporting the efficacy of sixdifferent drugs: fluoxetine, fluvoxamine, sertraline, paroxetine,citalopram, and escitalopram. However, patients with migraine are alsotreated with triptans, and potentially life-threatening SerotoninSyndrome may develop as the result of the combined administration ofSSRIs and triptans [Randolph W. Evans. The FDA Alert on SerotoninSyndrome With Combined Use of SSRIs or SNRIs and Triptans: An Analysisof the 29 Case Reports. MedGenMed 9(3, 2007): 48]. Accordingly, there isa need for new anxiety disorders treatments, particularly in individualswith co-morbid migraine. The presently disclosed methods and devicesinvolving vagal nerve stimulation (VNS) are intended as such atreatment. The present invention differs from other VNS treatments foranxiety disorders in that it may be performed non-invasively, includingusing magnetic stimulation to the vagus nerve, and in that it involvesmodulation of glutamate or glutamate receptors (e.g., Pathways 83 inFIG. 9).

As described above, migraine headaches are due in part to hypoactivityof the sympathetic nervous system, as evidenced for example by reducednorepinephrine levels in migraineurs. More generally, in migraine thereis an imbalance between the sympathetic and parasympathetic nervoussystems in which the former is hypoactive and the latter is hyperactive.Stimulation of the vagus nerve as described herein is intended torestore the sympathetic/parasympathetic balance to a more normal range,for example by activating the locus ceruleus to increase sympatheticdischarge and inhibit parasympathetic tone through its connectionswithin the brainstem, or by activating a structure such as thehypothalamus that might restore autonomic balance. Such stimulation mayalso cause the release of catecholamines (epinephrine and/ornorepinephrine) from the adrenal glands and/or from nerve endings thatare distributed throughout the body, in which circulation primarilythrough the carotid artery delivers the catacholamines to the brain.

However, it is understood that the vagus nerve is not the only nerve ortissue that may be stimulated as a countermeasure against sympathetichypoactivity or sympathetic/parasympathetic imbalance. Commonly assignedco-pending patent applications US20070106338, entitled Direct andIndirect Control of Muscle for the Treatment of Pathologies to ERRICOand US20100249873, entitled Direct and Indirect Control of Muscle forthe Treatment of Pathologies, to ERRICO, contemplate the electricalstimulation of nerves emanating from a patient's sympathetic nervechain, as well as stimulation of the nerve plexus of fibers emanatingfrom both the sympathetic nerve chain and the tenth cranial nerve (thevagus nerve), such as the hepatic plexus. U.S. Pat. No. 7,418,292 toSHAFER also relates to electrical stimulation of neurons of thesympathetic nervous system. U.S. Pat. No. 7,877,146, entitled Methods oftreating medical conditions by neuromodulation of the sympatheticnervous system, to Rezai et al is concerned with the neuromodulation ofthe sympathetic nervous system to treat respiratory and pulmonaryconditions, but mentions treatment of migraine within a long list ofdiseases that may be treated. The stimulation of a branch of the greatersplanchnic nerve also causes release of catecholamines from the adrenalgland, in addition to direct electrical stimulation of that gland [XiGuo and Arun R. Wakade. Differential secretion of catecholamines inresponse to peptidergic and cholinergic transmitters in rat adrenals.Journal of Physiology 475(3, 1994):539-545].

In such applications involving sympathetic stimulation, the stimulatingelectrode would ordinarily be implanted invasively, but it is alsopossible to implant the stimulating electrodes percutaneously [Patentapplication US20100234907, entitled Splanchnic Nerve Stimulation forTreatment of Obesity, to Dobak]. Considering that the devices andmethods disclosed herein are intended for the stimulation of deepnerves, in situations where the introduction of electrodespercutaneously is feasible, the presently disclosed non-invasive devicesmay work as well.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. An apparatus for treating a primaryheadache in a patient, the apparatus comprising: a housing comprising anelectrically permeable contact surface configured to contact an outerskin surface of the patient; a source of energy configured to generatean electric field within the housing, wherein the electric field issufficient to transmit an electric current through the outer skinsurface of the patient to a vagus nerve of the patient, wherein theelectric current comprises bursts of pulses with each of the burstscomprising a frequency from about 1 Hz to about 100 Hz and with each ofthe pulses comprising a duration from about 100 microseconds to about400 microseconds; and wherein the electric current is sufficient togenerate an electric field at the vagus nerve, wherein the electricfield is above a threshold for generating an action potential within afiber of the vagus nerve, wherein the fiber is responsible foractivating a neural pathway to cause a release of an inhibitoryneurotransmitter within a brain of the patient to at least partiallyrelieve one or more symptoms of the primary headache.
 2. The apparatusof claim 1, wherein the housing further comprises one or more electrodesand a conduction medium positioned between the one or more electrodesand the electrically permeable contact surface.
 3. The apparatus ofclaim 2, wherein the conduction medium is positioned in electricalcontact with a portion of an outer surface of the housing to at leastpartially restrict a direction of the electric field generated by thesource of energy and the one or more electrodes.
 4. The apparatus ofclaim 2 wherein the conductive medium comprises a solution ofelectrolytes.
 5. The apparatus of claim 2 wherein the conductive mediumcomprises a conductive gel.
 6. The apparatus of claim 1, wherein each ofthe pulses is generated from a signal that is not modulated by anothersignal.
 7. The apparatus of claim 1, wherein each of the pulsescomprises a duration of about 200 microseconds.
 8. The apparatus ofclaim 1 wherein the source of energy comprises one or more electrodescoupled to a signal generator within the housing.
 9. The apparatus ofclaim 1, wherein the source of energy comprises one or more toroidswithin the housing, wherein the one or more toroids is configured togenerate a magnetic field sufficient to induce the electric field. 10.The apparatus of claim 1 wherein the housing is a handheld deviceconfigured for contacting a neck of a patient.
 11. The apparatus ofclaim 1, wherein the electric current is sufficient to at leastpartially relieve a pain associated with the primary headache.
 12. Theapparatus of claim 1 wherein the headache is a migraine headache. 13.The apparatus of claim 1 wherein the headache is a cluster headache. 14.The apparatus of claim 1 wherein the headache is a tension headache. 15.The apparatus of claim 1 wherein the headache is a sinus headache. 16.The apparatus of claim 1, wherein at least one of the pulses comprises asinusoidal waveform and a frequency from about 2.5 KHz to about 10 KHz.17. The apparatus of claim 16 wherein at least one of the pulsescomprises a frequency of about 5000 Hz.
 18. The apparatus of claim 1,wherein each of the bursts of pulses comprises a frequency from about 10Hz to about 35 Hz.
 19. The apparatus of claim 1, wherein the inhibitoryneurotransmitter comprises GABA.
 20. The apparatus of claim 1, whereinthe inhibitory neurotransmitter comprises serotonin.
 21. The apparatusof claim 1, wherein the inhibitory neurotransmitter comprisesnorepinephrine.
 22. The apparatus of claim 1, wherein a sufficient levelof the inhibitory neurotransmitter is released in the brain of thepatient to reduce a level of a glutamate in the brain.
 23. A methodcomprising: treating a primary headache in a patient, wherein thetreating comprises: accessing a device comprising a housing and a sourceof energy, wherein the housing comprises an electrically permeablecontact surface configured to contact an outer skin surface of thepatient, wherein the source of energy is configured to generate anelectric field within the housing, wherein the electric field issufficient to transmit an electric current through the outer skinsurface of the patient to a vagus nerve of the patient, wherein theelectric current comprises bursts of pulses with each of the burstscomprising a frequency from about 1 Hz to about 100 Hz and with each ofthe pulses comprising a duration from about 100 microseconds to about400 microseconds, wherein the electric current is sufficient to generatean electric field at the vagus nerve, wherein the electric field isabove a threshold for generating an action potential within a fiber ofthe vagus nerve, wherein the fiber is responsible for activating aneural pathway to cause a release of an inhibitory neurotransmitterwithin a brain of the patient to at least partially relieve one or moresymptoms of the primary headache; contacting the outer skin surface ofthe patient with the electrically permeable contact surface; andgenerating the electric field within the housing via the source ofenergy.